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    ABERCROMBIE, E., KEEFE, K., DIFRISCHIA, D. & ZIGMOND, M. DIFFERENTIAL EFFECT OF STRESS ON INVIVO DOPAMINE RELEASE IN STRIATUM, NUCLEUS ACCUMBENS, AND MEDIAL FRONTAL-CORTEX {1989} JOURNAL OF NEUROCHEMISTRY
    Vol. {52}({5}), pp. {1655-1658} 
    article  
    BibTeX:
    @article{ABERCROMBIE1989,
      author = {ABERCROMBIE, ED and KEEFE, KA and DIFRISCHIA, DS and ZIGMOND, MJ},
      title = {DIFFERENTIAL EFFECT OF STRESS ON INVIVO DOPAMINE RELEASE IN STRIATUM, NUCLEUS ACCUMBENS, AND MEDIAL FRONTAL-CORTEX},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1989},
      volume = {52},
      number = {5},
      pages = {1655-1658}
    }
    
    Adams, B. & Moghaddam, B. Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine {1998} JOURNAL OF NEUROSCIENCE
    Vol. {18}({14}), pp. {5545-5554} 
    article  
    Abstract: The behavioral syndrome produced by phencyclidine (PCP) and its analog ketamine represents a pharmacological model for some aspects of schizophrenia. Despite the multifaceted properties of these drugs, the main mechanism for their psychotomimetic and cognitive-impairing effects has been thought heretofore to involve the corticolimbic dopamine system. The present study examined the temporal relationship between alterations in corticolimbic dopamine and glutamate neurotransmission and two dopamine-dependent behavioral effects of PCP in the rodent that have relevance to the clinical phenomenology, namely, impairment of working memory, which is used to model the frontal lobe deficits associated with schizophrenia, and hyperlocomotion, which is used as a predictor of the propensity of a drug to elicit or exacerbate psychosis. PCP increased dopamine and glutamate efflux in the prefrontal cortex and nucleus accumbens, as measured by microdialysis. The increase in dopamine in both regions remained elevated well above baseline 2.5 hr after the injection, at which time the experiment was terminated. However, locomotor activity returned to baseline in <2 hr after injection. Furthermore, impaired performance in a discrete trial delayed alternation task, a rodent working memory task, was only evident up to 60 min after PCP injection; animals tested 80 min after injection, when cortical dopamine release was elevated at 300% of baseline, did not exhibit impaired performance. These findings indicate that activation of dopamine neurotransmission is not sufficient to sustain PCP-induced locomotion and impairment of working memory. Thus, effects of PCP, including a glutamatergic hyperstimulation, may be necessary to account for the psychotomimetic and cognitive-impairing effects of this drug.
    BibTeX:
    @article{Adams1998,
      author = {Adams, B and Moghaddam, B},
      title = {Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1998},
      volume = {18},
      number = {14},
      pages = {5545-5554}
    }
    
    Aharon, I., Etcoff, N., Ariely, D., Chabris, C., O'Connor, E. & Breiter, H. Beautiful faces have variable reward value: fMRI and behavioral evidence {2001} NEURON
    Vol. {32}({3}), pp. {537-551} 
    article  
    Abstract: The brain circuitry processing rewarding and aversive stimuli is hypothesized to be at the core of motivated behavior. In this study, discrete categories of beautiful faces are shown to have differing reward values and to differentially activate reward circuitry in human subjects. In particular, young heterosexual males rate pictures of beautiful males and females as attractive, but exert effort via a keypress procedure only to view pictures of attractive females. Functional magnetic resonance imaging at 3 T shows that passive viewing of beautiful female faces activates reward circuitry, in particular the nucleus accumbens. An extended set of subcortical and paralimbic reward regions also appear to follow aspects of the keypress rather than the rating procedures, suggesting that reward circuitry function does not include aesthetic assessment.
    BibTeX:
    @article{Aharon2001,
      author = {Aharon, I and Etcoff, N and Ariely, D and Chabris, CF and O'Connor, E and Breiter, HC},
      title = {Beautiful faces have variable reward value: fMRI and behavioral evidence},
      journal = {NEURON},
      year = {2001},
      volume = {32},
      number = {3},
      pages = {537-551}
    }
    
    ALBIN, R., MAKOWIEC, R., HOLLINGSWORTH, Z., DURE, L., PENNEY, J. & YOUNG, A. EXCITATORY AMINO-ACID BINDING-SITES IN THE BASAL GANGLIA OF THE RAT - A QUANTITATIVE AUTORADIOGRAPHIC STUDY {1992} NEUROSCIENCE
    Vol. {46}({1}), pp. {35-48} 
    article  
    Abstract: Quantitative receptor autoradiography was used to determine the distribution of excitatory amino acid binding sites in the basal ganglia of rat brain. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid, N-methyl-D-aspartate, kainate, quisqualate-sensitive etabotropic and non-N-methyl-D-aspartate, non-kainate, non-quisqualate glutamate binding sites had their highest density in striatum, nucleus accumbens, and olfactory tubercle. Kainate binding was higher in the lateral striatum but there was no medial-lateral striatal gradient for other binding sites. N-Methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding sites were most dense in the nucleus accumbens and olfactory tubercle. There was no dorsal-ventral gradient within the striatal complex for the other binding sites. Other regions of the basal ganglia had lower densities of ligand binding. To compare binding site density within non-striatal regions, binding for each ligand was normalized to the striatal binding density. When compared to the striatal complex, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and metabotropic binding sites had higher relative density in the globus pallidus, ventral pallidum, and subthalamic nucleus than other binding sites. Metabotropic binding also had a high relative density in the substantia nigra. Non-N-methyl-D-aspartate, non-kainate, non-quisqualate glutamate binding sites had a high relative density in globus pallidus, ventral pallidum, and substantia nigra. N-Methyl-D-aspartate binding sites had a low relative density in pallidum, subthalamic nucleus, substantia nigra and ventral tegmental area. Our data indicate heterogeneous distribution of excitatory amino acid binding sites within rat basal ganglia and suggest that the character of excitatory amino acid-mediated neurotransmission within the basal ganglia is also heterogeneous.
    BibTeX:
    @article{ALBIN1992,
      author = {ALBIN, RL and MAKOWIEC, RL and HOLLINGSWORTH, ZR and DURE, LS and PENNEY, JB and YOUNG, AB},
      title = {EXCITATORY AMINO-ACID BINDING-SITES IN THE BASAL GANGLIA OF THE RAT - A QUANTITATIVE AUTORADIOGRAPHIC STUDY},
      journal = {NEUROSCIENCE},
      year = {1992},
      volume = {46},
      number = {1},
      pages = {35-48}
    }
    
    Altman, J., Everitt, B., Glautier, S., Markou, A., Nutt, D., Oretti, R., Phillips, G. & Robbins, T. The biological, social and clinical bases of drug addiction: Commentary and debate {1996} PSYCHOPHARMACOLOGY
    Vol. {125}({4}), pp. {285-345} 
    article  
    Abstract: This article summarizes the main discussions at a meeting on the biological, social and clinical bases of drug addiction focused on contemporary topics in drug dependence. Four main domains are surveyed, reflecting the structure of the meeting: psychological and pharmacological factors; neurobiological substrates; risk factors (including a consideration of vulnerability from an environmental and genetic perspective); and clinical treatment. Among the topics discussed were tolerance, sensitization, withdrawal, craving and relapse; mechanisms of reinforcing actions of drugs at the behavioural, cognitive and neural levels; the role of subjective factors in drug dependence; approaches to the behavioural and molecular genetics of drug dependence; the use of functional neuroimaging; pharmaceutical and psychosocial strategies for treatment; epidemiological and sociological aspects of drug dependence. The survey takes into account the considerable disagreements and controversies arising from the discussions, but also reaches a degree of consensus in certain areas.
    BibTeX:
    @article{Altman1996,
      author = {Altman, J and Everitt, BJ and Glautier, S and Markou, A and Nutt, D and Oretti, R and Phillips, GD and Robbins, TW},
      title = {The biological, social and clinical bases of drug addiction: Commentary and debate},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1996},
      volume = {125},
      number = {4},
      pages = {285-345}
    }
    
    APICELLA, P., LJUNGBERG, T., SCARNATI, E. & SCHULTZ, W. RESPONSES TO REWARD IN MONKEY DORSAL AND VENTRAL STRIATUM {1991} EXPERIMENTAL BRAIN RESEARCH
    Vol. {85}({3}), pp. {491-500} 
    article  
    Abstract: The sources of input and the behavioral effects of lesions and drug administration suggest that the striatum participates in motivational processes. We investigated the activity of single striatal neurons of monkeys in response to reward delivered for performing in a go-nogo task. A drop of liquid was given each time the animal correctly executed or withheld an arm movement in reaction to a visual stimulus. Of 1593 neurons, 115 showed increased activity in response to delivery of liquid reward in both go and nogo trials. Responding neurons were predominantly located in dorsal and ventromedial parts of anterior putamen, in dorsal and ventral caudate, and in nucleus accumbens. They were twice as frequent in ventral as compared to dorsal striatal areas. Responses occurred at a median latency of 337 ms and lasted for 525 ms, with insignificant differences between dorsal and ventral striatum. Reward responses differed from activity recorded in the face area of posterior putamen which varied synchronously with individual mouth movements. Responses were directly related to delivery of primary liquid reward and not to auditory stimuli associated with it. Most of them also occurred when reward was delivered outside of the task. These results demonstrate that neurons of dorsal and particularly ventral striatum are involved in processing information concerning the attribution of primary reward.
    BibTeX:
    @article{APICELLA1991,
      author = {APICELLA, P and LJUNGBERG, T and SCARNATI, E and SCHULTZ, W},
      title = {RESPONSES TO REWARD IN MONKEY DORSAL AND VENTRAL STRIATUM},
      journal = {EXPERIMENTAL BRAIN RESEARCH},
      year = {1991},
      volume = {85},
      number = {3},
      pages = {491-500}
    }
    
    ARNOLD, S., HYMAN, B., VANHOESEN, G. & DAMASIO, A. SOME CYTOARCHITECTURAL ABNORMALITIES OF THE ENTORHINAL CORTEX IN SCHIZOPHRENIA {1991} ARCHIVES OF GENERAL PSYCHIATRY
    Vol. {48}({7}), pp. {625-632} 
    article  
    Abstract: The cytoarchitecture of the entorhinal cortex was examined in the brains of six patients with a diagnosis of schizophrenia and in 16 controls. All six brains of schizophrenic patients showed abnormalities of the rostral and intermediate portions of the entorhinal cortex. The abnormalities included aberrant invaginations of the surface, disruption of cortical layers, heterotopic displacement of neurons, and paucity of neurons in superficial layers. These changes suggest disturbed development. Because the entorhinal cortex is pivotal for neural systems that mediate corticohippocampal interactions, early disruption of its structure could lead to important neuropsychological changes during development and in adult life and could contribute to the symptomatology of schizophrenia.
    BibTeX:
    @article{ARNOLD1991,
      author = {ARNOLD, SE and HYMAN, BT and VANHOESEN, GW and DAMASIO, AR},
      title = {SOME CYTOARCHITECTURAL ABNORMALITIES OF THE ENTORHINAL CORTEX IN SCHIZOPHRENIA},
      journal = {ARCHIVES OF GENERAL PSYCHIATRY},
      year = {1991},
      volume = {48},
      number = {7},
      pages = {625-632}
    }
    
    ARTOLA, A. & SINGER, W. LONG-TERM DEPRESSION OF EXCITATORY SYNAPTIC TRANSMISSION AND ITS RELATIONSHIP TO LONG-TERM POTENTIATION {1993} TRENDS IN NEUROSCIENCES
    Vol. {16}({11}), pp. {480-487} 
    article  
    Abstract: In many brain areas, including the cerebellar cortex, neocortex, hippocampus, striatum and nucleus accumbens, brief activation of an excitatory pathway can produce long-term depression (LTD) of synaptic transmission. In most preparations, induction of LTD has been shown to require a minimum level of postsynaptic depolarization and a rise in the intracellular Ca2+ concentration [Ca2+]i in the postsynaptic neurone. Thus, induction conditions resemble those described for the initiation of associative long-term potentiation (LTP). However, data from structures susceptible to both LTD and LTP suggest that a stronger depolarization and a greater increase in [Ca2+]i are required to induce LTP than to initiate LTD. The source of Ca2+ appears to be less critical for the differential induction of LTP and LTD than the amplitude of the Ca2+ surge, since the activation of voltage- and ligand-gated Ca2+ conductances as well as the release from intracellular stores have all been shown to contribute to both LTD and LTP induction. LTD is induceable even at inactive synapses if [Ca2+]i is raised to the appropriate level by antidromic or heterosynaptic activation, or by raising the extracellular Ca2+ concentration [Ca2+]o. These conditions suggest a rule (called here the ABS rule) for activity-dependent synaptic modifications that differs from the classical Hebb rule and that can account for both homosynaptic LTD and LTP as well as for heterosynaptic competition and associativity.
    BibTeX:
    @article{ARTOLA1993,
      author = {ARTOLA, A and SINGER, W},
      title = {LONG-TERM DEPRESSION OF EXCITATORY SYNAPTIC TRANSMISSION AND ITS RELATIONSHIP TO LONG-TERM POTENTIATION},
      journal = {TRENDS IN NEUROSCIENCES},
      year = {1993},
      volume = {16},
      number = {11},
      pages = {480-487}
    }
    
    ASCHER, J., COLE, J., COLIN, J., FEIGHNER, J., FERRIS, R., FIBIGER, H., GOLDEN, R., MARTIN, P., POTTER, W., RICHELSON, E. & SULSER, F. BUPROPION - A REVIEW OF ITS MECHANISM OF ANTIDEPRESSANT ACTIVITY {1995} JOURNAL OF CLINICAL PSYCHIATRY
    Vol. {56}({9}), pp. {395-401} 
    article  
    Abstract: Background: The mechanism of action of the novel antidepressant bupropion remains unclear after many years of study. A review of the relevant biochemical, in vivo brain microdialysis, electrophysiologic, behavioral, and clinical data clarifies what is known about this unique compound and suggests possible modes of action. Method: A panel of 11 experts was convened for a conference to discuss bupropion's mechanism of antidepressant activity. Four of the panelists presented current research findings, followed by a discussion. Results: (1) Biochemical studies suggest down-regulation of postsynaptic beta-adrenoceptors and desensitization of the norepinephrine-stimulated adenylate cyclase in the rat cortex occur only after chronic administration of very high doses of bupropion. (2) In vivo brain microdialysis studies demonstrate that, after chronic administration, there is an enhancement of bupropion-induced increases in extracellular dopamine in the nucleus accumbens. (3) Electrophysiologic data show that with acute dosing, bupropion reduces the firing rates of noradrenergic neurons in the locus ceruleus, The firing rates of dopaminergic neurons are reduced by bupropion in the A9 and A10 areas of the brain, but only at very high doses, and bupropion does not alter the firing rates of serotonergic neurons in the dorsal raphe, (4) Behavioral studies show that the most active metabolite of bupropion, hydroxybupropion (306U73), appears to be responsible for a large part of the compound's effects in animal models of antidepressant activity. (5) Clinical studies indicate that bupropion enhances noradrenergic functional activity as reflected by an increased excretion of the hydroxy metabolite of melatonin, while at the same time producing a presumably compensatory decrease in norepinephrine turnover. In one study, bupropion elevated plasma levels of the dopamine metabolite homovanillic acid in nonresponders, but not in responders. Conclusion: The mechanism of action of bupropion appears to have an unusual, not fully understood, noradrenergic link. The bupropion metabolite hydroxybupropion probably plays a critical role in bupropion's antidepressant activity, which appears to be predominantly associated with long-term noradrenergic effects. The mild central nervous system activating effects of bupropion appear to be due to weak dopaminergic mechanisms. There is some evidence that dopamine may contribute to bupropion's antidepressant properties. Antidepressant effects of bupropion are not serotonergically mediated.
    BibTeX:
    @article{ASCHER1995,
      author = {ASCHER, JA and COLE, JO and COLIN, JN and FEIGHNER, JP and FERRIS, RM and FIBIGER, HC and GOLDEN, RN and MARTIN, P and POTTER, WZ and RICHELSON, E and SULSER, F},
      title = {BUPROPION - A REVIEW OF ITS MECHANISM OF ANTIDEPRESSANT ACTIVITY},
      journal = {JOURNAL OF CLINICAL PSYCHIATRY},
      year = {1995},
      volume = {56},
      number = {9},
      pages = {395-401}
    }
    
    Ashby, F., Isen, A. & Turken, U. A neuropsychological theory of positive affect and its influence on cognition {1999} PSYCHOLOGICAL REVIEW
    Vol. {106}({3}), pp. {529-550} 
    article  
    Abstract: Positive affect systematically influences performance on many cognitive tasks. A new neuropsychological theory is proposed that accounts for many of these effects by assuming that positive affect is associated with increased brain dopamine levels. The theory predicts or accounts for influences of positive affect on olfaction, the consolidation of long-term (i.e., episodic) memories, working memory, and creative problem solving. For example, the theory assumes that creative problem solving is improved, in part, because increased dopamine release in the anterior cingulate improves cognitive flexibility and facilitates the selection of cognitive perspective.
    BibTeX:
    @article{Ashby1999,
      author = {Ashby, FG and Isen, AM and Turken, U},
      title = {A neuropsychological theory of positive affect and its influence on cognition},
      journal = {PSYCHOLOGICAL REVIEW},
      year = {1999},
      volume = {106},
      number = {3},
      pages = {529-550}
    }
    
    Baker, D., McFarland, K., Lake, R., Shen, H., Tang, X., Toda, S. & Kalivas, P. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse {2003} NATURE NEUROSCIENCE
    Vol. {6}({7}), pp. {743-749} 
    article DOI  
    Abstract: Repeated cocaine treatment and withdrawal produces changes in brain function thought to be involved in relapse to drug use. Withdrawal from repeated cocaine reduced in vivo extracellular glutamate in the nucleus accumbens of rats by decreasing the exchange of extracellular cystine for intracellular glutamate. In vivo restoration of cystine/glutamate exchange by intracranial perfusion of cystine or systemically administered N-acetylcysteine normalized the levels of glutamate in cocaine-treated subjects. To determine if the reduction in nonvesicular glutamate release is a mediator of relapse, we examined cocaine-primed reinstatement of drug seeking after cocaine self-administration was stopped. Reinstatement was prevented by stimulating cystine/glutamate exchange with N-acetylcysteine and restoring extracellular glutamate. Thus, withdrawal from repeated cocaine increases susceptibility to relapse in part by reducing cystine/glutamate exchange, and restoring exchanger activity prevents cocaine-primed drug seeking.
    BibTeX:
    @article{Baker2003,
      author = {Baker, DA and McFarland, K and Lake, RW and Shen, H and Tang, XC and Toda, S and Kalivas, PW},
      title = {Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse},
      journal = {NATURE NEUROSCIENCE},
      year = {2003},
      volume = {6},
      number = {7},
      pages = {743-749},
      doi = {{10.1038/nn1069}}
    }
    
    BAKSHI, V., SWERDLOW, N. & GEYER, M. CLOZAPINE ANTAGONIZES, PHENCYCLIDINE-INDUCED DEFICITS IN SENSORIMOTOR GATING OF THE STARTLE RESPONSE {1994} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {271}({2}), pp. {787-794} 
    article  
    Abstract: Intense auditory stimuli elicit an involuntary startle response that is attenuated when the startling stimulus (the pulse) is preceded immediately by a low intensity stimulus (the prepulse). This phenomenon of prepulse inhibition (PPI) is utilized as a measure of sensorimotor gating and is significantly reduced in schizophrenic patients. Noncompetitive N-methyl-D-aspartate antagonists such as phencyclidine (PCP) and (+)5-methyl-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5,1O-imine (dizocilpine or MK-801) have been found previously to disrupt PPI in animals. The present investigation assessed the ability of several antipsychotic drugs to reverse PCP-induced deficits in PPI in rats. Animals were pretreated with either the atypical antipsychotic clozapine (0, 1.25, 2.5, 5.0 or 10.0 mg/ kg), the D2 dopamine antagonist raclopride (0, 0.1 or 0.5 mg/ kg), the D1 dopamine antagonist SCH23390 (0, 0.01 or 0.05 mg/kg) or the 5-hydroxytryptamine(2) antagonists ritanserin (0 or 2.0 mg/kg) or ketanserin (0 or 1.0 mg/kg) and then were given PCP (1.0 mg/kg). After drug administration, animals were tested in startle chambers. PCP repeatedly and robustly decreased PPI without affecting base-line startle reactivity. Clozapine (5.0 mg/kg) antagonized this effect of PCP without altering PPI by itself. Raclopride, SCH23390, ritanserin and ketanserin were ineffective at reversing the PCP-induced deficit in PPI. As with PCP, 0.1 mg/kg of MK-801 disrupted PPI; this disruption also was antagonized by 5.0 mg/kg of clozapine. Thus, it appears that the ability of clozapine to reverse deficits in PPI produced by noncompetitive N-methyl-D-aspartate antagonists cannot be attributed to a sole antagonism of either D1 dopamine, D2 dopamine or 5-hydroxytryptamine(2) receptors. Rather, simultaneous antagonistic properties at multiple receptors and neurotransmitter systems may underlie the efficacy of clozapine. The PCP-induced disruption of PPI may serve as a useful model with which to study possible novel treatments for sensorimotor gating abnormalities in schizophrenia.
    BibTeX:
    @article{BAKSHI1994,
      author = {BAKSHI, VP and SWERDLOW, NR and GEYER, MA},
      title = {CLOZAPINE ANTAGONIZES, PHENCYCLIDINE-INDUCED DEFICITS IN SENSORIMOTOR GATING OF THE STARTLE RESPONSE},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1994},
      volume = {271},
      number = {2},
      pages = {787-794}
    }
    
    BALSKUBIK, R., ABLEITNER, A., HERZ, A. & SHIPPENBERG, T. NEUROANATOMICAL SITES MEDIATING THE MOTIVATIONAL EFFECTS OF OPIOIDS AS MAPPED BY THE CONDITIONED PLACE PREFERENCE PARADIGM IN RATS {1993} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {264}({1}), pp. {489-495} 
    article  
    Abstract: An unbiased conditioned place preference paradigm was used to examine the neuroanatomical substrates mediating the reinforcing and aversive effects of mu and kappa opioid agonists. Unilateral microinjection of the selective mu agonist DAMGO into the ventral tegmental area (VTA), the origin of the mesolimbic and mesocortical dopamine (DA) systems, resulted in dose-dependent preferences for the drug-associated place. Intracranial injections of DAMGO into terminal projection sites of VTA DA neurons, the nucleus accumbens and the medial prefrontal cortex, however, as well as into the lateral hypothalamus, were without effect. In contrast, microinjections of the kappa agonist U50,488H and the dynorphin derivative E-2078 into the VTA produced place aversions. Place aversions were also observed after microinjections of U50,488H and E-2078 into the nucleus accumbens, medial prefrontal cortex and lateral hypothalamus. However, microinjections of mu and kappa agonists into either the origin of the mesostriatal DA system, the substantia nigra or into its major terminal field, the nucleus caudatus-putamen, was without effect. Autoradiographic studies revealed that the substances remained within a restricted area around the injection site, confirming that the effects observed were mediated therein. Thus, these data suggest an important role for the A10 neurons in the VTA in the regulation of both mu and kappa opioid-induced motivational states. The rewarding effects are associated with the activation of mu receptors in the VTA, whereas aversive effects are associated with the activation Of kappa receptors in the VTA and its limbic-cortical terminal regions.
    BibTeX:
    @article{BALSKUBIK1993,
      author = {BALSKUBIK, R and ABLEITNER, A and HERZ, A and SHIPPENBERG, TS},
      title = {NEUROANATOMICAL SITES MEDIATING THE MOTIVATIONAL EFFECTS OF OPIOIDS AS MAPPED BY THE CONDITIONED PLACE PREFERENCE PARADIGM IN RATS},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1993},
      volume = {264},
      number = {1},
      pages = {489-495}
    }
    
    Bardo, M. Neuropharmacological mechanisms of drug reward: Beyond dopamine in the nucleus accumbens {1998} CRITICAL REVIEWS IN NEUROBIOLOGY
    Vol. {12}({1-2}), pp. {37-67} 
    article  
    Abstract: Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens io the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.
    BibTeX:
    @article{Bardo1998,
      author = {Bardo, MT},
      title = {Neuropharmacological mechanisms of drug reward: Beyond dopamine in the nucleus accumbens},
      journal = {CRITICAL REVIEWS IN NEUROBIOLOGY},
      year = {1998},
      volume = {12},
      number = {1-2},
      pages = {37-67}
    }
    
    Bardo, M. & Bevins, R. Conditioned place preference: what does it add to our preclinical understanding of drug reward? {2000} PSYCHOPHARMACOLOGY
    Vol. {153}({1}), pp. {31-43} 
    article  
    Abstract: Rationale: Among the various experimental protocols that have been used to measure drug reward in laboratory animals, conditioned place preference (CPP) has been one of the most popular. However, a number of controversial issues have surrounded the use of this experimental protocol. Objective: The present review provides a theoretical overview of some critical issues relevant to CPP. The advantages and limitations of CPP are also covered. Results: Based on modern and traditional theoretical formulations of Pavlovian conditioning, CPP appears to reflect a preference for a context due to the contiguous association between the context and a drug stimulus. Within this theoretical framework, it seems clear that CPP measures a learning process that is fundamentally distinct from drug self-administration. The main advantages of CPP are that it: (1) tests animals in a drug-free state; (2) is sensitive to both reward and aversion; (3) allows for simultaneous determination of CPP and locomotor activity; (4) is adaptable to a variety of species; (5) typically yields dose-effect curves that are monophasic rather than biphasic; and (6) has utility in probing the neural circuits involved in drug reward. The main limitations of CPP are that it: (1) is subject to interpretation based on the notion of novelty seeking; (2) is cumbersome for providing the graded dose-effect curves needed for answering some pharmacological questions; (3) is difficult to interpret when animals prefer one context prior to drug conditioning; and (4) lacks face validity as an experimental protocol of drug reward in humans. Conclusion: Despite some limitations, CPP provides unique information about the rewarding effect of contextual cues associated with a drug stimulus.
    BibTeX:
    @article{Bardo2000,
      author = {Bardo, MT and Bevins, RA},
      title = {Conditioned place preference: what does it add to our preclinical understanding of drug reward?},
      journal = {PSYCHOPHARMACOLOGY},
      year = {2000},
      volume = {153},
      number = {1},
      pages = {31-43}
    }
    
    Bardo, M., Donohew, R. & Harrington, N. Psychobiology of novelty seeking and drug seeking behavior {1996} BEHAVIOURAL BRAIN RESEARCH
    Vol. {77}({1-2}), pp. {23-43} 
    article  
    Abstract: There is considerable evidence that high novelty seekers are at increased risk for using drugs of abuse relative to low novelty seekers. This review examines the potential biological mechanism that may help explain the relationship between novelty seeking and drug seeking behavior. Evidence is summarized to suggest that exposure to novelty activates, at least in part, the same neural substrate that mediates the rewarding effects of drugs of abuse. It is argued that individual differences in response to novelty and drugs may relate to individual differences in the mesolimbic dopamine (DA) system of the brain. Individual differences in both novelty seeking and drug seeking behavior, while under some degree of genetic control, appear to be modifiable by early developmental experiences and this modification may relate to alterations in activity of the mesolimbic DA system. Within the context of this biological formulation, implications for the prevention and treatment of drug abuse are discussed.
    BibTeX:
    @article{Bardo1996,
      author = {Bardo, MT and Donohew, RL and Harrington, NG},
      title = {Psychobiology of novelty seeking and drug seeking behavior},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {1996},
      volume = {77},
      number = {1-2},
      pages = {23-43}
    }
    
    Bassareo, V. & Di Chiara, G. Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments {1999} NEUROSCIENCE
    Vol. {89}({3}), pp. {637-641} 
    article  
    Abstract: The nucleus accumbens septi is the major target of mesolimbic dopamine neurons originating in the ventral tegmental area of the mesencephalon.(3) Studies involving experimental manipulation of dopamine transmission by drugs and by lesions, as well as in vivo monitoring of extracellular dopamine concentrations, have provided evidence that the dopamine transmission of the nucleus accumbens plays an important role in behaviour motivated by conventional (e.g., food, sex)(22,23,29) and drug reinforcers.(6,14) Motivated behaviour is distinguished into an appetitive (preparatory/anticipatory) phase consisting of flexible response patterns intended to search and approach the reward itself, and a consummatory phase, consisting of fixed response patterns (eating, drinking, copulating, etc.) finalized to the utilization of the biological resources of the reward (caloric, metabolic, genetic, etc.)(13) While some studies reported a stimulation of dopamine transmission in the nucleus accumbens in relation to appetitive as well as consummatory behaviour,(7,19) other studies reported a relationship exclusively with consummatory behaviour.(10,16,20,28) Therefore, the precise relationship between dopamine transmission in the nucleus accumbens and specific phases of motivated behaviour is debated. On the basis of topographical, histochemical and connectional evidence, the nucleus accumbens has been subdivided into two compartments, medioventral ``shell'' and a laterodorsal ``core''.(1,8,9,11) This heterogeneity may be relevant to the current debate over the role of nucleus accumbens dopamine in behaviour. Thus, one might hypothesize that, depending on the specific compartment of the nucleus accumbens where dopamine transmission is monitored, a different relationship with specific stimuli which motivate behaviour is obtained. In order to verify this possibility we monitored by microdialysis(4,27) the changes in dopamine transmission in the nucleus accumbens shell and core during appetitive and consummatory phases of behaviour motivated by food. As food we utilized a palatable snack food (Fonzies) whose consumption has been shown in previous studies from our laboratory to release dopamine in the nucleus accumbens shell and in the medial prefrontal cortex.(2) Unpredicted consumption of Fonzies preferentially stimulated dopamine transmission in the shell as compared to the core. Appetitive food stimuli (perforated Fonzies-filled boxes) phasically stimulated dopamine transmission in the core but not in the shell and sensitized the dopamine response to feeding in the core but inhibited that in the shell. These clear-cut differences between nucleus accumbens shell and core suggest that phasic dopamine transmission in each compartment of the nucleus accumbens subserves different roles in motivated behaviour. (C) 1999 IBRO. Published by Elsevier Science Ltd.
    BibTeX:
    @article{Bassareo1999,
      author = {Bassareo, V and Di Chiara, G},
      title = {Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments},
      journal = {NEUROSCIENCE},
      year = {1999},
      volume = {89},
      number = {3},
      pages = {637-641}
    }
    
    Bassareo, V. & DiChiara, G. Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum {1997} JOURNAL OF NEUROSCIENCE
    Vol. {17}({2}), pp. {851-861} 
    article  
    Abstract: Feeding a novel food (Fonzies) to rats fed ad libitum with standard food increased extracellular dopamine (DA) in the medial prefrontal cortex (PFCX) and in the medial nucleus accumbens (NAc). Previous Fonzies feeding, although it did not affect the increase of extracellular DA in the PFCX in response to Fonzies feeding, blunted that increase in the NAc (habituation); recovery from habituation in the NAc was complete 5 d after previous Fonzies feeding. Predictive association of an otherwise neutral stimulus extrinsic to Fonzies (empty plastic box) with Fonzies feeding resulted in the acquisition by the stimulus of the property to elicit incentive responses directed toward the stimulus and to increase extracellular DA in the PFCX. However, the same stimulus, or a more complex stimulus including intrinsic stimuli (Fonzies-filled plastic box), failed to acquire the ability to modify extracellular DA in the NAc. Pseudoconditioning, i.e., nonpredictive association of the extrinsic stimulus (empty box) with Fonzies feeding, did not result in acquisition by the stimulus of the property to elicit incentive responses and to increase extracellular DA in the PFCX. Repeated nonreinforced presentation of previously conditioned extrinsic stimuli (empty box) resulted in extinction of the property to elicit incentive responses and to increase extracellular DA in the PFCX. These results indicate that in rats fed ad libitum, phasic activation of mesocortical and mesolimbic DA systems by motivational stimuli is differentially influenced by associative (conditioning) and nonassociative (habituation) learning mechanisms and is differentially related to acquisition and expression of incentive motivation.
    BibTeX:
    @article{Bassareo1997,
      author = {Bassareo, V and DiChiara, G},
      title = {Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1997},
      volume = {17},
      number = {2},
      pages = {851-861},
      note = {European-Behavioral-Pharmacology-Society Meeting, CAGLIARI, ITALY, 1996}
    }
    
    Baxter, M. & Murray, E. The amygdala and reward {2002} NATURE REVIEWS NEUROSCIENCE
    Vol. {3}({7}), pp. {563-573} 
    article DOI  
    Abstract: The amygdala - an almond-shaped group of nuclei at the heart of the telencephalon has been associated with a range of cognitive functions, including emotion, learning, memory, attention and perception. Most current views of amygdala function emphasize its role in negative emotions, such as fear, and in linking negative emotions with other aspects of cognition, such as learning and memory. However, recent evidence supports a role for the amygdala in processing positive emotions as well as negative ones, including learning about the beneficial biological value of stimuli. Indeed, the amygdala's role in stimulus-reward learning might be just as important as its role in processing negative affect and fear conditioning.
    BibTeX:
    @article{Baxter2002,
      author = {Baxter, MG and Murray, EA},
      title = {The amygdala and reward},
      journal = {NATURE REVIEWS NEUROSCIENCE},
      year = {2002},
      volume = {3},
      number = {7},
      pages = {563-573},
      doi = {{10.1038/nrn875}}
    }
    
    BECK, C. & FIBIGER, H. CONDITIONED FEAR-INDUCED CHANGES IN BEHAVIOR AND IN THE EXPRESSION OF THE IMMEDIATE-EARLY GENE C-FOS - WITH AND WITHOUT DIAZEPAM PRETREATMENT {1995} JOURNAL OF NEUROSCIENCE
    Vol. {15}({1, Part 2}), pp. {709-720} 
    article  
    Abstract: The synthesis of Fos, the protein product of the immediate early gene c-fos, was used to map metabolically some of the neural substrates of conditioned fear in the rat. analysis of the behaviors emitted by the rats during the test session provided strong evidence that the conditioning procedure was effective. Exposure to the environment in which they had previously received footshock significantly increased the number of Fos-like immunoreactive neurons in nearly 50 brain regions, both cortical and subcortical. Among the structures showing the most dramatic increases in fear-induced c-fos expression were the cingulate, piriform, infralimbic, and retrosplenial cortices, the anterior olfactory nucleus, claustrum, endopiriform nucleus, nucleus accumbens shell, lateral septal nucleus, various amygdalar nuclei, paraventricular thalamic nucleus, ventral lateral geniculate nucleus, the ventromedial, lateral, and dorsal hypothalamic nuclei, the ventral tegmental area, and the supramammillary area. These data demonstrate that a relatively simple classical conditioning procedure activates a large number of widely dispersed cortical and subcortical structures. Some of the structures showing increased c-fos expression have important autonomic functions and may therefore have reflected centrally mediated changes in blood pressure and respiration produced by the anxiogenic stimuli. In a second experiment, the effects of pretreatment with the anxiolytic drug diazepam (2.5, 5.0, or 10 mg/kg) were evaluated. The benzodiazepine produced dose-related decreases in the frequency of crouching (freezing) elicited by the aversively conditioned contextual cues. Diazepam also produced dose-related decreases in conditioned stress-induced c-fos expression in all but one structure, the effects being statistically significant in 38 of 60 sampled structures. Diazepam dose dependently increased fear-induced c-fos expression in the central nucleus of the amygdala. There was considerable regional variability with respect to sensitivity to diazepam, the retrosplenial cortex and the supramammillary area being the only two structures to show decreases after the lowest dose of diazepam. In contrast, the entorhinal cortex, nucleus accumbens core, ventromedial and posterior hypothalamic nuclei, median raphe, and locus coeruleus were particularly resistant to diazepam, all failing to show statistically significant decreases in conditioned fear-induced c-fos expression even at the highest dose. The extent to which diazepam decreased conditioned stress-induced c-fos expression was unrelated to previous estimates of benzodiazepine receptor density in the sampled structures.
    BibTeX:
    @article{BECK1995,
      author = {BECK, CHM and FIBIGER, HC},
      title = {CONDITIONED FEAR-INDUCED CHANGES IN BEHAVIOR AND IN THE EXPRESSION OF THE IMMEDIATE-EARLY GENE C-FOS - WITH AND WITHOUT DIAZEPAM PRETREATMENT},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1995},
      volume = {15},
      number = {1, Part 2},
      pages = {709-720}
    }
    
    Becker, J. Gender differences in dopaminergic function in striatum and nucleus accumbens {1999} PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
    Vol. {64}({4}), pp. {803-812} 
    article  
    Abstract: In female rats the gonadal hormones estrogen and progesterone modulate dopamine (DA) activity in the striatum and nucleus accumbens. For example, there is estrous cycle-dependent variation in basal extracellular concentration of striatal DA, in amphetamine (AMPH)-stimulated DA release, and in striatal DA-mediated behaviors. Ovariectomy attenuates basal extracellular DA, AMPH-induced striatal DA release, and behaviors mediated by the striatal DA system. Estrogen rapidly and directly acts on the striatum and accumbens, via a G-protein-coupled external membrane receptor, to enhance DA release and DA-mediated behaviors. In male rats, estrogen does not affect striatal DA release, and removal of testicular hormones is without effect. These effects of estrogen also result in gender differences in sensitization to psychomotor stimulants. The effects of the gonadal hormones on the striatum and ascending DA systems projecting to the striatum and nucleus accumbens are hypothesized to occur as follows: estrogen induces a rapid change in neuronal excitability by acting on membrane receptors located in intrinsic striatal GABAergic neurons and on DA terminals. The effect of these two actions results in enhanced stimulated DA release through modulation of terminal excitability. These effects of gonadal hormones are postulated to have important implications for gender differences in susceptibility to addiction to the psychomotor stimulants. It is suggested that hormonal modulation of the striatum may have evolved to facilitate reproductive success in female rats by enhancing pacing behavior. (C) 1999 Elsevier Science Inc.
    BibTeX:
    @article{Becker1999,
      author = {Becker, JB},
      title = {Gender differences in dopaminergic function in striatum and nucleus accumbens},
      journal = {PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR},
      year = {1999},
      volume = {64},
      number = {4},
      pages = {803-812}
    }
    
    BENLOUCIF, S. & GALLOWAY, M. FACILITATION OF DOPAMINE RELEASE INVIVO BY SEROTONIN AGONISTS - STUDIES WITH MICRODIALYSIS {1991} EUROPEAN JOURNAL OF PHARMACOLOGY
    Vol. {200}({1}), pp. {1-8} 
    article  
    Abstract: Using microdialysis, changes in extraneuronal levels of dopamine (DA), and the metabolites of DA and serotonin (5-HT), were monitored concurrent with perfusion of 5-HT1 agonists into the anterior striata of anesthetized rats. Perfusion of 5-HT facilitated DA release in a dose dependent manner, and to a greater extent than any other agonist tested. Extraneuronal DA levels increased 34% with perfusion of 0.04 nmol 5-HT and 18-fold with perfusion of 4.0 nmol 5-HT. Perfusion with multiple doses of either 1-(m-chlorophenyl)piperazine (m-CPP) or trifluoromethylphenylpiperazine (TFMPP) also resulted in a dose-dependent facilitation of DA release with a 40% increase in extracellular DA produced by either 0.4 nmol m-CPP or 10.0 nmol TFMPP. A 50-fold increase in DA followed 40.0 nmol m-CPP, while 160 nmol TFMPP enhanced DA 11-fold. Local application of either 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate (RU24969) or 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) (2.0 nmol perfused over 20 min) increased extracellular DA by 300 and 40 respectively. RU24969 (2.0 nmol) also facilitated DA release following systemic pretreatment with 8-OH-DPAT (100-mu-g/kg). Perfusion with fenfluramine to release endogenous 5-HT also increased extraneuronal DA in a dose-dependent manner, and this facilitation was prevented by pretreatment with the 5-HT reuptake inhibitor fluoxetine. The facilitation of DA release by 0.4 nmol 5-HT was reduced by pretreatment with the 5-HT1 antagonist pindolol (4.0 nmol). These results suggest that serotonergic innervation of the anterior striatum may exert a facilatory influence on DA release.
    BibTeX:
    @article{BENLOUCIF1991,
      author = {BENLOUCIF, S and GALLOWAY, MP},
      title = {FACILITATION OF DOPAMINE RELEASE INVIVO BY SEROTONIN AGONISTS - STUDIES WITH MICRODIALYSIS},
      journal = {EUROPEAN JOURNAL OF PHARMACOLOGY},
      year = {1991},
      volume = {200},
      number = {1},
      pages = {1-8}
    }
    
    BENLOUCIF, S., KEEGAN, M. & GALLOWAY, M. SEROTONIN-FACILITATED DOPAMINE RELEASE INVIVO - PHARMACOLOGICAL CHARACTERIZATION {1993} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {265}({1}), pp. {373-377} 
    article  
    Abstract: The receptor specificity of serotonin (5-HT) agonist-induced facilitation of dopamine (DA) release was assessed by using in vivo microdialysis. The 5-HT receptor selective agonists RU 24969 [5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate], 2-methylserotonin maleate, 5-methoxytryptamine HCl, 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCI were perfused through probes located in the anterior lateral striata of chloral hydrate-anesthetized rats. The agonists increased extra-neuronal levels of DA in a dose-dependent manner, suggesting receptor selectivity in the order of 5-HT1b > 5-HT4 >> 5-HT2 = 5-HT1a. Coperfusion of the 5-HT1 antagonist pindolol with RU 24969 reduced the efficacy of RU 24969. The 5-HT2 antagonist ritanserin (6-[2-[4[bis(4-fluorophenyl)methylene]-l-piperadinyl]-ethyl]-7-met hYl-5H-thiazolo[3,2-a]pyrimidin-5-one) did not antagonize the effect of either 5-HT or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCI on DA levels. MDL 72222 (3-tropanyl-3,5-dichlorobenzoate) and ICS 205930 (3-tropanyl-indole-3-carboxylate), both 5-HT3 antagonists, decreased the efficacy of 5-HT. The partial 5-HT4 antagonist ICS 205930 reduced DA released by perfusion of the 5-HT1/2/4 agonist 5-methoxytryptamine HCI. Coperfusion of antagonists with agonists indicated involvement of 5-HT1 and 5-HT3 receptors and a lack of involvement of 5-HT2 receptors in the 5-HT-induced facilitation of DA release. Determination of the role of 5-HT4 receptors will require additional work with more selective ligands. Together, these results support a specific receptor-mediated role for 5-HT in the facilitation of DA release.
    BibTeX:
    @article{BENLOUCIF1993,
      author = {BENLOUCIF, S and KEEGAN, MJ and GALLOWAY, MP},
      title = {SEROTONIN-FACILITATED DOPAMINE RELEASE INVIVO - PHARMACOLOGICAL CHARACTERIZATION},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1993},
      volume = {265},
      number = {1},
      pages = {373-377}
    }
    
    BENWELL, M. & BALFOUR, D. THE EFFECTS OF ACUTE AND REPEATED NICOTINE TREATMENT ON NUCLEUS-ACCUMBENS DOPAMINE AND LOCOMOTOR-ACTIVITY {1992} BRITISH JOURNAL OF PHARMACOLOGY
    Vol. {105}({4}), pp. {849-856} 
    article  
    Abstract: 1 The effects of acute and subchronic nicotine and (+)-amphetamine on the extracellular levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens (NAc) have been studied in conscious, freely-moving rats by use of in vivo microdialysis. 2 In rats which had been habituated to the test apparatus for approximately 80 min, the acute subcutaneous (s.c.) administration of nicotine (0.1 or 0.4 mg kg-1) caused a dose-dependent increase (P < 0.01) in spontaneous activity and evoked significant increases (P < 0.05) in the extracellular levels of DOPAC and HVA. 3 Measurements made 24 h after the last injection of nicotine showed that pretreatment with the higher doses tested (0.4 mg kg-1) resulted in increased basal levels of dopamine (P < 0.01) and decreased basal levels of DOPAC (P < 0.05) in the NAc dialysates. 4 Pretreatment with nicotine (0.1 or 0.4 mg kg-1 daily for 5 days) enhanced the effects of the drug on spontaneous locomotor activity and enhanced the effects of the drug on extracellular levels of dopamine to the extent that the response became significant (P < 0.05). 5 If a dopamine uptake inhibitor, nomifensine, was added to the Ringer solution used to dialyse the probe, the s.c. administration of both acute and subchronic nicotine (0.4 mg kg-1) resulted in significant increases (P < 0.05) in the dopamine concentration in the dialysate. Under these conditions, pretreatment with nicotine prior to the test day prolonged (P < 0.05) the dopamine response to a challenge dose of nicotine. 6 Subcutaneous injections of (+)-amphetamine (0.2 or 0.5 mg kg-1) evoked dose-dependent increases in both spontaneous activity and the concentration of dopamine in NAc dialysates. These responses were unaffected by 5 days pretreatment with the drug. 7 The results of this study support the conclusion that the enhanced locomotor response to nicotine observed in animals pretreated with the drug prior to the test day is associated with potentiation of its effects on dopamine secretion in the NAc.
    BibTeX:
    @article{BENWELL1992,
      author = {BENWELL, MEM and BALFOUR, DJK},
      title = {THE EFFECTS OF ACUTE AND REPEATED NICOTINE TREATMENT ON NUCLEUS-ACCUMBENS DOPAMINE AND LOCOMOTOR-ACTIVITY},
      journal = {BRITISH JOURNAL OF PHARMACOLOGY},
      year = {1992},
      volume = {105},
      number = {4},
      pages = {849-856}
    }
    
    BERENDSE, H., GALISDEGRAAF, Y. & GROENEWEGEN, H. TOPOGRAPHICAL ORGANIZATION AND RELATIONSHIP WITH VENTRAL STRIATAL COMPARTMENTS OF PREFRONTAL CORTICOSTRIATAL PROJECTIONS IN THE RAT {1992} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {316}({3}), pp. {314-347} 
    article  
    Abstract: The anterograde tracer Phaseolus vulgaris-leucoagglutinin was used to examine the topographical organization of the projections to the striatum arising from the various cytoarchitectonic subdivisions of the prefrontal cortex in the rat. The relationship of the prefrontal cortical fibres with the compartmental organization of the ventral striatum was assessed by combining PHA-L tracing and enkephalin-immunohistochemistry. The prefrontal cortex projects bilaterally with an ipsilateral predominance to the striatum, sparing only the lateral part of the caudate-putamen complex. Each of the cytoarchitectonic subfields of the prefrontal cortex has a longitudinally oriented striatal terminal field that overlaps slightly with those of adjacent prefrontal areas. The projections of the medial subdivision of the prefrontal cortex distribute to rostral and medial parts of the striatum, whereas the lateral prefrontal subdivision projects to more caudal and lateral striatal areas. The terminal fields of the orbital prefrontal areas involve midventral and ventromedial parts of the caudate-putamen complex. The projection of the ventral orbital area overlaps with that of the prelimbic area in the ventromedial part of the caudate-putamen. In the ``shell'' region of the nucleus accumbens, fibres arising from the prelimbic area concentrate in areas of high cell density that are weakly enkephalin-immunoreactive, whereas fibres from the infralimbic area avoid such areas. Rostrolaterally in the ``core'' region of the nucleus accumbens, fibres from deep layer V and layer VI of the dorsal part of the prelimbic area avoid the enkephalin-positive areas surrounding the anterior commissure and distribute in an inhomogeneous way over the intervening moderately enkephalin-immunoreactive compartment. The other prefrontal afferents show only a preference for, but are not restricted to, the latter compartment. In the border region between the nucleus accumbens and the ventromedial part of the caudate-putamen complex, patches of strong enkephalin immunoreactivity receive prefrontal cortical input from deep layer V and layer VI, whereas fibres from more superficial cortical layers project to the surrounding matrix. Individual eytoarchitectonic subfields of the prefrontal cortex thus have circumscribed terminal domains in the striatum. In combination with data on the organization of the midline and intralaminar thalamostriatal and thalamoprefrontal projections, the present results establish that the projections of the prefrontal cortical subfields converge in the striatum with those of their midline and intralaminar afferent nuclei. The present findings further demonstrate that the relationship of the prefrontal corticostriatal fibres with the neurochemical compartments of the ventral striatum can be influenced by both the areal and the laminar origin of the cortical afferents, depending on the particular ventral striatal region under consideration.
    BibTeX:
    @article{BERENDSE1992,
      author = {BERENDSE, HW and GALISDEGRAAF, Y and GROENEWEGEN, HJ},
      title = {TOPOGRAPHICAL ORGANIZATION AND RELATIONSHIP WITH VENTRAL STRIATAL COMPARTMENTS OF PREFRONTAL CORTICOSTRIATAL PROJECTIONS IN THE RAT},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1992},
      volume = {316},
      number = {3},
      pages = {314-347}
    }
    
    Berke, J. & Hyman, S. Addiction, dopamine, and the molecular mechanisms of memory {2000} NEURON
    Vol. {25}({3}), pp. {515-532} 
    article  
    BibTeX:
    @article{Berke2000,
      author = {Berke, JD and Hyman, SE},
      title = {Addiction, dopamine, and the molecular mechanisms of memory},
      journal = {NEURON},
      year = {2000},
      volume = {25},
      number = {3},
      pages = {515-532}
    }
    
    Berns, G., McClure, S., Pagnoni, G. & Montague, P. Predictability modulates human brain response to reward {2001} JOURNAL OF NEUROSCIENCE
    Vol. {21}({8}), pp. {2793-2798} 
    article  
    Abstract: Certain classes of stimuli, such as food and drugs, are highly effective in activating reward regions. We show in humans that activity in these regions can be modulated by the predictability of the sequenced delivery of two mildly pleasurable stimuli, orally delivered fruit juice and water. Using functional magnetic resonance imaging, the activity for rewarding stimuli in both the nucleus accumbens and medial orbitofrontal cortex was greatest when the stimuli were unpredictable. Moreover, the subjects' stated preference for either juice or water was not directly correlated with activity in reward regions but instead was correlated with activity in sensorimotor cortex. For pleasurable stimuli, these findings suggest that predictability modulates the response of human reward regions, and subjective preference can be dissociated from this response.
    BibTeX:
    @article{Berns2001,
      author = {Berns, GS and McClure, SM and Pagnoni, G and Montague, PR},
      title = {Predictability modulates human brain response to reward},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2001},
      volume = {21},
      number = {8},
      pages = {2793-2798}
    }
    
    Berridge, K. Food reward: Brain substrates of wanting and liking {1996} NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
    Vol. {20}({1}), pp. {1-25} 
    article  
    Abstract: What are the neural substrates of food reward? Are reward and pleasure identical? Can taste pleasure be assessed in animals? Is reward necessarily conscious? These questions have re-emerged in recent years, and there is now sufficient evidence to prompt re-examination of many preconceptions concerning reward and its relation to brain systems. This paper reviews evidence from many sources regarding both the psychological structure of food reward and the neural systems that mediate it. Special attention is paid to recent evidence from `'taste reactivity'' studies of affective reactions to food. I argue that this evidence suggests the following surprising possibilities regarding the functional components and brain substrates of food reward. (1) Reward contains distinguishable psychological or functional components-''liking'' (pleasure/palatability) and `'wanting'' (appetite/incentive motivation). These can be manipulated and measured separately. (2) Liking and wanting have separable neural substrates. Mediation of liking related to food reward involves neurotransmitter systems such as opioid and GABA/benzodiazepine systems, and anatomical structures such as ventral pallidum and brainstem primary gustatory relays. Mediation of wanting related to food reward involves mesotelencephalic dopamine systems, and divisions of nucleus accumbens and amygdala. Both liking and wanting arise from vastly distributed neural systems, but the two systems are separable. (3) Neural processing of food reward is not confined to the limbic forebrain. Aspects of food reward begin to be processed in the brainstem. A neural manipulation can enhance reward or produce aversion but no single lesion or transection is likely abolish all properties of food reward. (4) Both wanting and liking can exist without subjective awareness. Conscious experience can distort or blur the underlying reward processes that gave rise to it. Subjective reports may contain false assessments of underlying processes, or even fail at all to register important reward processes. The core processes of liking and wanting that constitute reward are distinct from the subjective report or conscious awareness of those processes.
    BibTeX:
    @article{Berridge1996,
      author = {Berridge, KC},
      title = {Food reward: Brain substrates of wanting and liking},
      journal = {NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS},
      year = {1996},
      volume = {20},
      number = {1},
      pages = {1-25}
    }
    
    Berridge, K. & Robinson, T. Parsing reward {2003} TRENDS IN NEUROSCIENCES
    Vol. {26}({9}), pp. {507-513} 
    article DOI  
    Abstract: Advances in neurobiology permit neuroscientists to manipulate specific brain molecules, neurons and systems. This has lead to major advances in the neuroscience of reward. Here, it is argued that further advances will require equal sophistication in parsing reward into its specific psychological components: (1) learning (including explicit and implicit knowledge produced by associative conditioning and cognitive processes); (2) affect or emotion (implicit `liking' and conscious pleasure) and (3) motivation (implicit incentive salience `wanting' and cognitive incentive goals). The challenge is to identify how different brain circuits mediate different psychological components of reward, and how these components interact.
    BibTeX:
    @article{Berridge2003,
      author = {Berridge, KC and Robinson, TE},
      title = {Parsing reward},
      journal = {TRENDS IN NEUROSCIENCES},
      year = {2003},
      volume = {26},
      number = {9},
      pages = {507-513},
      doi = {{10.1016/S0166-2236(03)00233-9}}
    }
    
    Berridge, K. & Robinson, T. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? {1998} BRAIN RESEARCH REVIEWS
    Vol. {28}({3}), pp. {309-369} 
    article  
    Abstract: What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is `no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the `taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs, quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for `wanting' incentives, but not for `liking' them or for learning new `likes' and `dislikes'. (C) 1998 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{Berridge1998,
      author = {Berridge, KC and Robinson, TE},
      title = {What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {1998},
      volume = {28},
      number = {3},
      pages = {309-369}
    }
    
    Berridge, K.C. The debate over dopamine's role in reward: the case for incentive salience {2007} PSYCHOPHARMACOLOGY
    Vol. {191}({3}), pp. {391-431} 
    article DOI  
    Abstract: Debate continues over the precise causal contribution made by mesolimbic dopamine systems to reward. There are three competing explanatory categories: `liking', learning, and `wanting'. Does dopamine mostly mediate the hedonic impact of reward ('liking')? Does it instead mediate learned predictions of future reward, prediction error teaching signals and stamp in associative links (learning)? Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli ('wanting')? Each hypothesis is evaluated here, and it is suggested that the incentive salience or `wanting' hypothesis of dopamine function may be consistent with more evidence than either learning or `liking'. In brief, recent evidence indicates that dopamine is neither necessary nor sufficient to mediate changes in hedonic `liking' for sensory pleasures. Other recent evidence indicates that dopamine is not needed for new learning, and not sufficient to directly mediate learning by causing teaching or prediction signals. By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal `wanting', and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short circuit and sensitize dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals. That interaction sets the stage to cause compulsive `wanting' in addiction, but also provides opportunities for experiments to disentangle `wanting', `liking', and learning hypotheses. Results from studies that exploited those opportunities are described here.
    BibTeX:
    @article{Berridge2007,
      author = {Berridge, Kent C.},
      title = {The debate over dopamine's role in reward: the case for incentive salience},
      journal = {PSYCHOPHARMACOLOGY},
      year = {2007},
      volume = {191},
      number = {3},
      pages = {391-431},
      doi = {{10.1007/s00213-006-0578-x}}
    }
    
    Berton, O., McClung, C., DiLeone, R., Krishnan, V., Renthal, W., Russo, S., Graham, D., Tsankova, N., Bolanos, C., Rios, M., Monteggia, L., Self, D. & Nestler, E. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress {2006} SCIENCE
    Vol. {311}({5762}), pp. {864-868} 
    article DOI  
    Abstract: Mice experiencing repeated aggression develop a long-tasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential rote for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.
    BibTeX:
    @article{Berton2006,
      author = {Berton, O and McClung, CA and DiLeone, RJ and Krishnan, V and Renthal, W and Russo, SJ and Graham, D and Tsankova, NM and Bolanos, CA and Rios, M and Monteggia, LM and Self, DW and Nestler, EJ},
      title = {Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress},
      journal = {SCIENCE},
      year = {2006},
      volume = {311},
      number = {5762},
      pages = {864-868},
      doi = {{10.1126/science.1120972}}
    }
    
    Berton, O. & Nestler, E. New approaches to antidepressant drug discovery: beyond monoamines {2006} NATURE REVIEWS NEUROSCIENCE
    Vol. {7}({2}), pp. {137-151} 
    article DOI  
    Abstract: All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only similar to 50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.
    BibTeX:
    @article{Berton2006a,
      author = {Berton, O and Nestler, EJ},
      title = {New approaches to antidepressant drug discovery: beyond monoamines},
      journal = {NATURE REVIEWS NEUROSCIENCE},
      year = {2006},
      volume = {7},
      number = {2},
      pages = {137-151},
      doi = {{10.1038/nrn1846}}
    }
    
    Bibb, J., Chen, J., Taylor, J., Svenningsson, P., Nishi, A., Snyder, G., Yan, Z., Sagawa, Z., Ouimet, C., Nairn, A., Nestler, E. & Greengard, P. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5 {2001} NATURE
    Vol. {410}({6826}), pp. {376-380} 
    article  
    Abstract: Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine re-uptake at axon terminals. Most dopamine-containing nerve terminals innervate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equilibrium by countering the effects of repeated drug administration(1,2). Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioural changes(1-4). One such transcription factor is Delta FosB, a protein that persists in striatum long after the end of cocaine exposure(3,5). Here we identify cyclin-dependent kinase 5 (Cdk5) as a downstream target gene of Delta FosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of Delta FosB, or chronic cocaine administration, raised levels of Cdk5 messenger RNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum potentiated behavioural effects of repeated cocaine administration. Our results suggest that changes in Cdk5 levels mediated by Delta FosB, and resulting alterations in signalling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.
    BibTeX:
    @article{Bibb2001,
      author = {Bibb, JA and Chen, JS and Taylor, JR and Svenningsson, P and Nishi, A and Snyder, GL and Yan, Z and Sagawa, ZK and Ouimet, CC and Nairn, AC and Nestler, EJ and Greengard, P},
      title = {Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5},
      journal = {NATURE},
      year = {2001},
      volume = {410},
      number = {6826},
      pages = {376-380}
    }
    
    Blood, A. & Zatorre, R. Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion {2001} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {98}({20}), pp. {11818-11823} 
    article  
    Abstract: We used positron emission tomography to study neural mechanisms underlying intensely pleasant emotional responses to music. Cerebral blood flow changes were measured in response to subject-selected music that elicited the highly pleasurable experience of ``shivers-down-the-spine'' or ``chills.'' Subjective reports of chills were accompanied by changes in heart rate, electromyogram, and respiration. As intensity of these chills increased, cerebral blood flow increases and decreases were observed in brain regions thought to be involved in reward/motivation, emotion, and arousal, including ventral striatum, midbrain, amygdala, orbitofrontal cortex, and ventral medial prefrontal cortex. These brain structures are known to be active in response to other euphoria-inducing stimuli, such as food, sex, and drugs of abuse. This finding links music with biologically relevant, survival-related stimuli via their common recruitment of brain circuitry involved in pleasure and reward.
    BibTeX:
    @article{Blood2001,
      author = {Blood, AJ and Zatorre, RJ},
      title = {Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {2001},
      volume = {98},
      number = {20},
      pages = {11818-11823}
    }
    
    BOUTHENET, M., SOUIL, E., MARTRES, M., SOKOLOFF, P., GIROS, B. & SCHWARTZ, J. LOCALIZATION OF DOPAMINE-D3 RECEPTOR MESSENGER-RNA IN THE RAT-BRAIN USING INSITU HYBRIDIZATION HISTOCHEMISTRY - COMPARISON WITH DOPAMINE-D2 RECEPTOR MESSENGER-RNA {1991} BRAIN RESEARCH
    Vol. {564}({2}), pp. {203-219} 
    article  
    Abstract: The messenger RNA (mRNA) of the recently characterized D3 dopamine receptor was visualized on rat brain sections using in situ hybridization with a P-32-labeled ribonucleic acid probe corresponding to a major part of the third cytoplasmic loop, a domain in which D2 and D3 dopamine receptors display little homology. For the purpose of comparison, D2 receptor mRNA was also specifically visualized on adjacent sections. The areas that expressed D2 and/or D3 receptors were also compared with those previously detected using [I-125]iodosulpride, a ligand that binds to both D2 and D3 receptors with a similar affinity. The localization of D3 receptor mRNa markedly differs from that of D2 receptor mRNA. Whereas D2 receptor mRNA is expressed in all major brain areas receiving dopaminergic projections, particularly in the whole striatal complex, D3 receptor mRNA is expressed in a more restricted manner. It is mainly detected in telencephalic areas receiving dopaminergic inputs from the A10 cell group, e.g. accumbens nucleus, islands of Calleja, bed nucleus of the stria terminalis and other limbic areas such as the hippocampus and the mammillary nuclei. D2 and D3 receptor mRNAs were also detected at the level of the substantia nigra, suggesting that these receptors function as both autoreceptor and postysnaptic receptors. In several dopaminergic projection areas, e.g. ventral striatum, septal or mammillary nuclei, the distributions of D2 and D3 receptor mRNAs appeared complementary without overlap. The distribution of [I-125]iodosulpride binding sites generally overlapped that of D2 or D3 receptor mRNAs, the latter being most abundant in dopaminergic areas known to be associated with cognitive and emotional functions.
    BibTeX:
    @article{BOUTHENET1991,
      author = {BOUTHENET, ML and SOUIL, E and MARTRES, MP and SOKOLOFF, P and GIROS, B and SCHWARTZ, JC},
      title = {LOCALIZATION OF DOPAMINE-D3 RECEPTOR MESSENGER-RNA IN THE RAT-BRAIN USING INSITU HYBRIDIZATION HISTOCHEMISTRY - COMPARISON WITH DOPAMINE-D2 RECEPTOR MESSENGER-RNA},
      journal = {BRAIN RESEARCH},
      year = {1991},
      volume = {564},
      number = {2},
      pages = {203-219}
    }
    
    BRAFF, D., GRILLON, C. & GEYER, M. GATING AND HABITUATION OF THE STARTLE REFLEX IN SCHIZOPHRENIC-PATIENTS {1992} ARCHIVES OF GENERAL PSYCHIATRY
    Vol. {49}({3}), pp. {206-215} 
    article  
    Abstract: Schizophrenic patients exhibit impairments in both sensorimotor gating and habituation in a number of paradigms. Through human and animal model research, these fundamental cognitive deficits have well-described neurobiologic bases and offer insights into the neuroanatomic and neurotransmitter abnormalities that characterize patients with schizophrenic spectrum disorders. In this context, the startle response is particularly interesting, because it is a cross-species response to strong stimuli that is plastic or alterable using experimental and neurobiologic manipulations. Thirty-nine medicated schizophrenic patients and 37 normal control subjects were studied in a new electromyography based startle response paradigm in which both prepulse inhibition (an operational measure of sensorimotor gating) and habituation (the normal decrease in response magnitude to repeated stimuli over time) can be separated and assessed in one test session. The results indicate that schizophrenic patients have extensive deficits in both intramodal and cross-modal sensorimotor gating and a trend to show acoustic startle habituation deficits. The deficit in prepulse inhibition of startle amplitude exhibited by schizophrenic patients was evident when an acoustic prepulse stimulus preceded either an acoustic or a tactile startle stimulus. No deficit was observed in the prepulse-induced facilitation of startle latencies, indicating that the failure of gating was not due to a failure of stimulus detection. These findings suggest centrally mediated deficits in sensorimotor gating in schizophrenic patients.
    BibTeX:
    @article{BRAFF1992,
      author = {BRAFF, DL and GRILLON, C and GEYER, MA},
      title = {GATING AND HABITUATION OF THE STARTLE REFLEX IN SCHIZOPHRENIC-PATIENTS},
      journal = {ARCHIVES OF GENERAL PSYCHIATRY},
      year = {1992},
      volume = {49},
      number = {3},
      pages = {206-215}
    }
    
    BREESE, G., DUNCAN, G., NAPIER, T., BONDY, S., IORIO, L. & MUELLER, R. 6-HYDROXYDOPAMINE TREATMENTS ENHANCE BEHAVIORAL-RESPONSES TO INTRACEREBRAL MICROINJECTION OF D1-DOPAMINE AND D2-DOPAMINE AGONISTS INTO NUCLEUS-ACCUMBENS AND STRIATUM WITHOUT CHANGING DOPAMINE ANTAGONIST BINDING {1987} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {240}({1}), pp. {167-176} 
    article  
    BibTeX:
    @article{BREESE1987,
      author = {BREESE, GR and DUNCAN, GE and NAPIER, TC and BONDY, SC and IORIO, LC and MUELLER, RA},
      title = {6-HYDROXYDOPAMINE TREATMENTS ENHANCE BEHAVIORAL-RESPONSES TO INTRACEREBRAL MICROINJECTION OF D1-DOPAMINE AND D2-DOPAMINE AGONISTS INTO NUCLEUS-ACCUMBENS AND STRIATUM WITHOUT CHANGING DOPAMINE ANTAGONIST BINDING},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1987},
      volume = {240},
      number = {1},
      pages = {167-176}
    }
    
    Breiter, H., Aharon, I., Kahneman, D., Dale, A. & Shizgal, P. Functional imaging of neural responses to expectancy and experience of monetary gains and losses {2001} NEURON
    Vol. {30}({2}), pp. {619-639} 
    article  
    Abstract: Neural responses accompanying anticipation and experience of monetary gains and losses were monitored by functional magnetic resonance imaging. Trials comprised an initial ``prospect'' (expectancy) phase, when a set of three monetary amounts was displayed, and a subsequent ``outcome'' phase, when one of these amounts was awarded. Hemodynamic responses in the sublenticular extended amygdala (SLEA) and orbital gyrus tracked the expected values of the prospects, and responses to the highest value set of outcomes increased monotonically with monetary value in the nucleus accumbens, SLEA, and hypothalamus. Responses to prospects and outcomes were generally, but not always, seen in the same regions. The overlap of the observed activations with those seen previously in response to tactile stimuli, gustatory stimuli, and euphoria-inducing drugs is consistent with a contribution of common circuitry to the processing of diverse rewards.
    BibTeX:
    @article{Breiter2001,
      author = {Breiter, HC and Aharon, I and Kahneman, D and Dale, A and Shizgal, P},
      title = {Functional imaging of neural responses to expectancy and experience of monetary gains and losses},
      journal = {NEURON},
      year = {2001},
      volume = {30},
      number = {2},
      pages = {619-639}
    }
    
    Breiter, H., Gollub, R., Weisskoff, R., Kennedy, D., Makris, N., Berke, J., Goodman, J., Kantor, H., Gastfriend, D., Riorden, J., Mathew, R., Rosen, B. & Hyman, S. Acute effects of cocaine on human brain activity and emotion {1997} NEURON
    Vol. {19}({3}), pp. {591-611} 
    article  
    Abstract: We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, Ventral tegmentum, and pens and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pens, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.
    BibTeX:
    @article{Breiter1997,
      author = {Breiter, HC and Gollub, RL and Weisskoff, RM and Kennedy, DN and Makris, N and Berke, JD and Goodman, JM and Kantor, HL and Gastfriend, DR and Riorden, JP and Mathew, RT and Rosen, BR and Hyman, SE},
      title = {Acute effects of cocaine on human brain activity and emotion},
      journal = {NEURON},
      year = {1997},
      volume = {19},
      number = {3},
      pages = {591-611}
    }
    
    BROG, J., SALYAPONGSE, A., DEUTCH, A. & ZAHM, D. THE PATTERNS OF AFFERENT INNERVATION OF THE CORE AND SHELL IN THE ACCUMBENS PART OF THE RAT VENTRAL STRIATUM - IMMUNOHISTOCHEMICAL DETECTION OF RETROGRADELY TRANSPORTED FLUOROGOLD {1993} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {338}({2}), pp. {255-278} 
    article  
    Abstract: Recent data have emphasized the neurochemically distinct nature of subterritories in the accumbens part of the rat ventral striatum termed the core, shell, and rostral pole. In order to gain a more comprehensive understanding of how afferents are distributed relative to these subterritories, immunohistochemical detection of retrogradely transported Fluoro-Gold was carried out following iontophoretic injections intended to involve selectively one of the subterritories. The data revealed that a number of cortical afferents of the medial shell and core originate in separate areas, i.e., the dorsal peduncular, infralimbic, and posterior piriform cortices (to medial shell) and the dorsal prelimbic, anterior agranular insular, anterior cingulate, and perirhinal cortices (to core). The lateral shell and rostral pole are innervated by cortical structures that also project either to the medial shell or core. The orbital, posterior agranular insular, and entorhinal cortices, hippocampus, and basal amygdala were observed to innervate the accumbens in a topographic manner. Following core injections, strong bilateral cortical labeling was observed. Few labeled cortical cells were observed contralaterally following injections in the medial shell. Intermediate numbers of labeled neurons were observed in contralateral cortices following lateral shell injections. Robust subcortical labeling in a variety of structures in the ventral forebrain, lateral hypothalamus, deep temporal lobe, and brainstem was observed after shell injections, particularly those that involved the caudal dorsomedial extremity of the shell, i.e., its `'septal pole.'' Selective ipsilateral labeling of subcortical structures in the basal ganglia circuitry was observed following injections in the core and, to a lesser extent, lateral shell. It was concluded that a number of afferent systems exhibit varying degrees of segregation with respect to the accumbal subterritories. (C) 1993 Wiley-Liss, Inc.
    BibTeX:
    @article{BROG1993,
      author = {BROG, JS and SALYAPONGSE, A and DEUTCH, AY and ZAHM, DS},
      title = {THE PATTERNS OF AFFERENT INNERVATION OF THE CORE AND SHELL IN THE ACCUMBENS PART OF THE RAT VENTRAL STRIATUM - IMMUNOHISTOCHEMICAL DETECTION OF RETROGRADELY TRANSPORTED FLUOROGOLD},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1993},
      volume = {338},
      number = {2},
      pages = {255-278}
    }
    
    BROUILLET, E., HANTRAYE, P., FERRANTE, R., DOLAN, R., LEROYWILLIG, A., KOWALL, N. & BEAL, M. CHRONIC MITOCHONDRIAL ENERGY IMPAIRMENT PRODUCES SELECTIVE STRIATAL DEGENERATION AND ABNORMAL CHOREIFORM MOVEMENTS IN PRIMATES {1995} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {92}({15}), pp. {7105-7109} 
    article  
    Abstract: Although the gene defect responsible for Huntington disease (HD) has recently been identified, the pathogenesis of the disease remains obscure. One potential mechanism is that the gene defect may lead to an impairment of energy metabolism followed by slow excitotoxic neuronal injury. In the present study we examined whether chronic administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, can replicate the neuropathologic and clinical features of HD in nonhuman primates. After 3-6 weeks of 3-NP administration, apomorphine treatment induced a significant increase in motor activity as compared with saline-treated controls. Animals showed both choreiform movements, as well as foot and limb dystonia, which are characteristic of HD. More prolonged 3-NP treatment in two additional primates resulted in spontaneous dystonia and dyskinesia accompanied by lesions in the caudate and putamen seen by magnetic resonance imaging. Histologic evaluation showed that there was a depletion of calbindin neurons, astrogliosis, sparing of NADPH-diaphorase neurons, and growth-related proliferative changes in dendrites of spiny neurons similar to changes in HD. The striosomal organization of the striatum and the nucleus accumbens were spared. These findings show that chronic administration of 3-NP to nonhuman primates can replicate many of the characteristic motor and histologic features of HD, further strengthening the possibility that a subtle impairment of energy metabolism may play a role in its pathogenesis.
    BibTeX:
    @article{BROUILLET1995,
      author = {BROUILLET, E and HANTRAYE, P and FERRANTE, RJ and DOLAN, R and LEROYWILLIG, A and KOWALL, NW and BEAL, MF},
      title = {CHRONIC MITOCHONDRIAL ENERGY IMPAIRMENT PRODUCES SELECTIVE STRIATAL DEGENERATION AND ABNORMAL CHOREIFORM MOVEMENTS IN PRIMATES},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1995},
      volume = {92},
      number = {15},
      pages = {7105-7109}
    }
    
    BROWN, E., ROBERTSON, G. & FIBIGER, H. EVIDENCE FOR CONDITIONAL NEURONAL ACTIVATION FOLLOWING EXPOSURE TO A COCAINE-PAIRED ENVIRONMENT - ROLE OF FOREBRAIN LIMBIC STRUCTURES {1992} JOURNAL OF NEUROSCIENCE
    Vol. {12}({10}), pp. {4112-4121} 
    article  
    Abstract: The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This form of classical conditioning is of considerable clinical relevance as intense craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. To understand better the neurobiology of cocaine-induced environment-specific conditioning, Fos expression was examined in the forebrain of rats exposed to an environment in which they had previously received cocaine. These results were compared to those observed following an acute injection of cocaine. Consistent with its stimulant actions, cocaine produced an increase in locomotion that was accompanied by an increase in Fos expression within specific limbic regions (cingulate cortex, claustrum, piriform cortex, lateral septal nucleus, paraventricular nucleus of the thalamus, lateral habenula, and amygdala) as well as the basal ganglia (dorsomedial striatum and nucleus accumbens). Exposure of rats to the cocaine-paired environment also produced an increase in locomotion, as compared to various control groups. In addition to this behavioral effect, conditioned subjects exhibited a significant increase in Fos expression within the cingulate cortex, claustrum, lateral septal nucleus, paraventricular nucleus of the thalamus, lateral habenula, and the amygdala, suggesting increased neuronal activity within these regions. In contrast to the dramatic effects observed within these structures, no conditional activation was observed within the piriform cortex, nucleus accumbens, or dorsal striatum, suggesting that these brain areas are not involved in the conditioned response. The present findings indicate that specific limbic regions exhibit increased neuronal activation during the presentation of cocaine-paired cues and may be involved in the formation of associations between cocaine's stimulant actions and the environment in which the drug administration occurred. Although the nucleus accumbens is necessary for the reinforcing and locomotor effects of cocaine, it does not exhibit a conditional Fos response, suggesting that different neural circuits are involved in the unconditioned and conditioned effects of cocaine.
    BibTeX:
    @article{BROWN1992,
      author = {BROWN, EE and ROBERTSON, GS and FIBIGER, HC},
      title = {EVIDENCE FOR CONDITIONAL NEURONAL ACTIVATION FOLLOWING EXPOSURE TO A COCAINE-PAIRED ENVIRONMENT - ROLE OF FOREBRAIN LIMBIC STRUCTURES},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1992},
      volume = {12},
      number = {10},
      pages = {4112-4121}
    }
    
    BURNS, L., ROBBINS, T. & EVERITT, B. DIFFERENTIAL-EFFECTS OF EXCITOTOXIC LESIONS OF THE BASOLATERAL AMYGDALA, VENTRAL SUBICULUM AND MEDIAL PREFRONTAL CORTEX ON RESPONDING WITH CONDITIONED REINFORCEMENT AND LOCOMOTOR-ACTIVITY POTENTIATED BY INTRAACCUMBENS INFUSIONS OF D-AMPHETAMINE {1993} BEHAVIOURAL BRAIN RESEARCH
    Vol. {55}({2}), pp. {167-183} 
    article  
    Abstract: The experiments reported here have investigated the impact on reward-related processes of lesioning the basolateral amygdala, ventral subiculum and prelimbic cortex which represent the major limbic sources of afferents to the ventral striatum. The results showed that, while lesions of the prelimbic cortex were without effect on the approach to a CS predictive of sucrose reinforcement and the acquisition of a new response with conditioned reinforcement, lesions of the other two structures significantly impaired both responses. However, there were important differences between the effects of basolateral amygdala and ventral subiculum lesions. Thus, lesions of the ventral subiculum completely abolished the locomotor response to intra-accumbens infusions Of D-amphetamine, in addition to blocking the potentiative effect of the same treatment on responding with conditioned reinforcement. Lesions of the basolateral amygdala, by contrast, reduced the control over behaviour by a conditioned reinforcer, but not the potentiation of that control by intra-accumbens D-amphetamine except at the highest dose. Moreover, the locomotor response to D-amphetamine-induced increases in dopamine in the nucleus accumbens was unaffected by amygdala lesions over the dose range blocked by ventral subiculum lesions. The results suggest a rather selective effect of amygdala-ventral striatal interactions on processes subserving conditioned reinforcement and a more fundamental influence of ventral subiculum-ventral striatal interactions in mediating the psychomotor stimulant effects Of D-amphetamine.
    BibTeX:
    @article{BURNS1993,
      author = {BURNS, LH and ROBBINS, TW and EVERITT, BJ},
      title = {DIFFERENTIAL-EFFECTS OF EXCITOTOXIC LESIONS OF THE BASOLATERAL AMYGDALA, VENTRAL SUBICULUM AND MEDIAL PREFRONTAL CORTEX ON RESPONDING WITH CONDITIONED REINFORCEMENT AND LOCOMOTOR-ACTIVITY POTENTIATED BY INTRAACCUMBENS INFUSIONS OF D-AMPHETAMINE},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {1993},
      volume = {55},
      number = {2},
      pages = {167-183}
    }
    
    Bymaster, F., Katner, J., Nelson, D., Hemrick-Luecke, S., Threlkeld, P., Heiligenstein, J., Morin, S., Gehlert, D. & Perry, K. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in Attention Deficit/Hyperactivity Disorder {2002} NEUROPSYCHOPHARMACOLOGY
    Vol. {27}({5}), pp. {699-711} 
    article  
    Abstract: The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K-i) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HTEX levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NEEX and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX). We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.
    BibTeX:
    @article{Bymaster2002,
      author = {Bymaster, FP and Katner, JS and Nelson, DL and Hemrick-Luecke, SK and Threlkeld, PG and Heiligenstein, JH and Morin, SM and Gehlert, DR and Perry, KW},
      title = {Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in Attention Deficit/Hyperactivity Disorder},
      journal = {NEUROPSYCHOPHARMACOLOGY},
      year = {2002},
      volume = {27},
      number = {5},
      pages = {699-711}
    }
    
    CADOR, M., BJIJOU, Y. & STINUS, L. EVIDENCE OF A COMPLETE INDEPENDENCE OF THE NEUROBIOLOGICAL SUBSTRATES FOR THE INDUCTION AND EXPRESSION OF BEHAVIORAL SENSITIZATION TO AMPHETAMINE {1995} NEUROSCIENCE
    Vol. {65}({2}), pp. {385-395} 
    article  
    Abstract: The repeated administration of amphetamine in rats produces behavioral sensitization which is characterized either by a progressive enhancement of the locomotor activity induced by the drug or by an enduring behavioral hypersensitivity to the drug after the cessation of the treatment. Some authors have suggested that the action of amphetamine at the level of the nucleus accumbens is responsible for the expression of behavioral sensitization, whereas the action of amphetamine at the level of the dopamine cell bodies in the ventral tegmental area induces some changes responsible for the initiation of the phenomenon. The present study fully tested this hypothesis. In two separate experiments, the effects of different doses of amphetamine repeatedly administered in the ventral tegmental area or in the nucleus accumbens were tested on the later behavioral reactivity to the administration of amphetamine in the nucleus accumbens. Independent groups of rats received five repeated administrations (one injection every other day) of different doses of amphetamine either in the ventral tegmental area (0, 1, 2.5, 5 mu g/0.5 mu 1 per side) or in the nucleus accumbens (0, 1, 3, 10 mu g/1 mu 1 per side). Two days following the last intracerebral amphetamine injection, each group received a phosphate buffer solution challenge directly into the nucleus accumbens followed two days later by an amphetamine challenge (1 mu g/1 mu 1 per side) in the nucleus accumbens and two days later by a peripheral challenge with amphetamine (0.5 mg/kg, s.c.), Locomotor responses were recorded following each injection. Results showed that injections of amphetamine into the nucleus accumbens induced a dose-dependent increase in locomotor activity which remained identical with the repetition of the injections. No difference between the different intra-accumbens pretreated groups was observed following the diverse phosphate-buffered saline solution and amphetamine challenges. In contrast, intra-ventral tegmental area administration of amphetamine did not produce any modification of locomotor activity. However, whereas no difference between the differently pretreated groups was observed following phosphate-buffered saline administration into the nucleus accumbens, a potentiation of the locomotor response to a challenge dose of amphetamine into the nucleus accumbens was observed which was dependent on the dose of amphetamine pretreatment into the ventral tegmental area. Similar potentiation was observed following peripheral challenge with amphetamine. Finally, cross-sensitization was observed when a challenge dose of cocaine (10 mu g/1 mu 1 per side) was injected into the nucleus accumbens, as well as when a peripheral challenge dose of morphine (2.5 mg/kg, s.c.) was administered to the ventral tegmental area-pretreated groups. Altogether, these results demonstrate that an amphetamine action solely at the level of the dopamine cell bodies in the ventral tegmental area is necessary and sufficient to promote changes subserving behavioral sensitization, which can be later revealed by an amphetamine action at the level of the dopamine terminals in the nucleus accumbens. On the contrary, the sole amphetamine action at the level of the nucleus accumbens is not sufficient to promote these changes but is necessary-to allow their expression. These findings argue for a complete dissociation for the neuroanatomical substrates which mediate the induction and the expression of the behavioral sensitization to amphetamine.
    BibTeX:
    @article{CADOR1995,
      author = {CADOR, M and BJIJOU, Y and STINUS, L},
      title = {EVIDENCE OF A COMPLETE INDEPENDENCE OF THE NEUROBIOLOGICAL SUBSTRATES FOR THE INDUCTION AND EXPRESSION OF BEHAVIORAL SENSITIZATION TO AMPHETAMINE},
      journal = {NEUROSCIENCE},
      year = {1995},
      volume = {65},
      number = {2},
      pages = {385-395}
    }
    
    CAINE, S. & KOOB, G. EFFECTS OF DOPAMINE D-1 AND D-2 ANTAGONISTS ON COCAINE SELF-ADMINISTRATION UNDER DIFFERENT SCHEDULES OF REINFORCEMENT IN THE RAT {1994} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {270}({1}), pp. {209-218} 
    article  
    Abstract: The effects of three dopamine D-1 receptor antagonists (SCH23390, SCH39166 and A69024) and three dopamine D-2 antagonists (raclopride, eticlopride and spiperone) on cocaine self-administration maintained under different schedules of reinforcement were examined in the rat. Intravenous cocaine self-administration was maintained under a fixed-ratio (FR) 5 schedule with a 20-sec timeout (TO) after each reinforcement or a FR 15 with a 2-min TO multiple schedule of cocaine (0.25 mg i.v.) and food (45 mg) reinforcement. With the exception of raclopride, all of the antagonists altered the self-administration of cocaine in a manner similar to decreasing the unit dose of cocaine under the schedule in effect, reflected by increased self-administration under the FR 5 TO 20-sec schedule and decreased self-administration under the FR 15 TO 2-min multiple schedule. Moreover, a low dose of either of the benzazepine dopamine D-1 antagonists SCH23390 or SCH39166, but not the other compounds, selectively reduced cocaine self-administration without altering responding for food under the multiple schedule. Conversely, a low dose of raclopride or A69024 selectively decreased food-reinforced responding without altering cocaine self-administration under the multiple schedule. These results suggest that benzazepine dopamine D-1 antagonists, at low doses, may attenuate the reinforcing properties of cocaine more selectively than other dopamine receptor antagonists. The results also demonstrate the advantages of using different schedules to investigate the effects of dopamine D-1 and D-2 antagonists on cocaine self-administration.
    BibTeX:
    @article{CAINE1994,
      author = {CAINE, SB and KOOB, GF},
      title = {EFFECTS OF DOPAMINE D-1 AND D-2 ANTAGONISTS ON COCAINE SELF-ADMINISTRATION UNDER DIFFERENT SCHEDULES OF REINFORCEMENT IN THE RAT},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1994},
      volume = {270},
      number = {1},
      pages = {209-218}
    }
    
    CAINE, S. & KOOB, G. MODULATION OF COCAINE SELF-ADMINISTRATION IN THE RAT THROUGH D-3 DOPAMINE-RECEPTORS {1993} SCIENCE
    Vol. {260}({5115}), pp. {1814-1816} 
    article  
    Abstract: The reinforcing properties of cocaine are probably mediated by the mesocorticolimbic dopamine pathways in the central nervous system, but not all of the dopamine receptor subtypes involved in cocaine's reinforcing actions have been clearly identified. Recently, the D-3 receptor has been cloned, and its distribution in the brain has been found to be relatively restricted to limbic projections of the midbrain dopamine system. The D-3-selective compounds 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT) and quinpirole potently decreased cocaine self-administration in the rat at doses that were not by themselves reinforcing. Moreover, three dopamine receptor agonists had affinities for binding to the D-3 receptor that correlated highly with their relative potencies in decreasing cocaine self-administration. The D-3 receptor may be involved in the reinforcing effects of cocaine and may be a useful target for the development of new pharmacotherapies for cocaine abuse.
    BibTeX:
    @article{CAINE1993,
      author = {CAINE, SB and KOOB, GF},
      title = {MODULATION OF COCAINE SELF-ADMINISTRATION IN THE RAT THROUGH D-3 DOPAMINE-RECEPTORS},
      journal = {SCIENCE},
      year = {1993},
      volume = {260},
      number = {5115},
      pages = {1814-1816}
    }
    
    CANTERAS, N., SIMERLY, R. & SWANSON, L. ORGANIZATION OF PROJECTIONS FROM THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS - A PHASEOLUS-VULGARIS-LEUKOAGGLUTININ STUDY IN THE RAT {1994} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {348}({1}), pp. {41-79} 
    article  
    Abstract: The organization of projections from the four parts of the ventromedial nucleus (VMH) and a ventrolaterally adjacent region tentatively identified as the tuberal nucleus (TU) have been analyzed with small injections of the anterograde axonal tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). Extrinsic and intranuclear projections of each part of the VMH display clear quantitative differences, whereas the overall patterns of outputs are qualitatively similar. Overall, the VMH establishes massive intrahypothalamic terminal fields in other parts of the medial zone, tending to avoid the periventricular and lateral zones. The ventrolateral VMH is more closely related to other parts of the hypothalamus that also express gonadal steroid hormone receptors, including the medial preoptic, tuberal, and ventral premamillary nuclei, whereas other parts of the VMH are more closely related to the anterior hypothalamic and dorsal premammillary nuclei. All parts of the VMH project to the zona incerta (including the A13 region) and parts of the midline thalamus, including the paraventricular and parataenial nuclei and nucleus reuniens. The densest inputs to the septum are to the bed nuclei of the stria terminalis, where the ventrolateral and central VMH innervate the anteroventral and anterodorsal areas and transverse and interfascicular nuclei, whereas the anterior and dorsomedial VMH innervate the latter two. The central, lateral, and medial amygdalar nuclei receive substantial inputs from various parts of the VMH. Other regions of the telencephalon, including the nucleus accumbens and the piriform-amygdaloid, infralimbic, prelimbic, anterior cingulate, agranular insular, piriform, perirhinal, entorhinal, and postpiriform transition areas, also receive sparse inputs. All parts of the VMH send a massive, topographically organized projection to the periaqueductal gray. Other brainstem terminal fields include the superior colliculus, peripeduncular area, locus coeruleus, Barrington's nucleus, parabrachial nucleus, nucleus of the solitary tract, and the mesencephalic, pontine, gigantocellular, paragigantocellular, and parvicellular reticular nuclei. The projections of the TU are similar to, and a subset of, those from the VMH and are thus not nearly as widespread as those from adjacent parts of the lateral hypothalamic area. Because of these similarities, the TU may eventually come to be viewed most appropriately as the lateral component of the VMH itself. The functional implications of the present findings are discussed in view of evidence that the VMH plays a role in the expression of ingestive, affective, and copulatory behaviors. (C) 1994 Wiley-Liss, Inc.
    BibTeX:
    @article{CANTERAS1994,
      author = {CANTERAS, NS and SIMERLY, RB and SWANSON, LW},
      title = {ORGANIZATION OF PROJECTIONS FROM THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS - A PHASEOLUS-VULGARIS-LEUKOAGGLUTININ STUDY IN THE RAT},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1994},
      volume = {348},
      number = {1},
      pages = {41-79}
    }
    
    CARBONI, E., IMPERATO, A., PEREZZANI, L. & DICHIARA, G. AMPHETAMINE, COCAINE, PHENCYCLIDINE AND NOMIFENSINE INCREASE EXTRACELLULAR DOPAMINE CONCENTRATIONS PREFERENTIALLY IN THE NUCLEUS ACCUMBENS OF FREELY MOVING RATS {1989} NEUROSCIENCE
    Vol. {28}({3}), pp. {653-661} 
    article  
    BibTeX:
    @article{CARBONI1989,
      author = {CARBONI, E and IMPERATO, A and PEREZZANI, L and DICHIARA, G},
      title = {AMPHETAMINE, COCAINE, PHENCYCLIDINE AND NOMIFENSINE INCREASE EXTRACELLULAR DOPAMINE CONCENTRATIONS PREFERENTIALLY IN THE NUCLEUS ACCUMBENS OF FREELY MOVING RATS},
      journal = {NEUROSCIENCE},
      year = {1989},
      volume = {28},
      number = {3},
      pages = {653-661}
    }
    
    Cardinal, R., Parkinson, J., Hall, J. & Everitt, B. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex {2002} NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
    Vol. {26}({3}), pp. {321-352} 
    article  
    Abstract: Emotions are multifaceted, but a key aspect of emotion involves the assessment of the value of environmental stimuli. This article reviews the many psychological representations, including representations of stimulus value, which are formed in the brain during Pavlovian and instrumental conditioning tasks. These representations may be related directly to the functions of cortical and subcortical neural structures. The basolateral amygdala (BLA) appears to be required for a Pavlovian conditioned stimulus (CS) to gain access to the current value of the specific unconditioned stimulus (US) that it predicts, while the central nucleus of the amygdala acts as a controller of brainstem arousal and response systems, and subserves some forms of stimulus-response Pavlovian conditioning. The nucleus accumbens, which appears not to be required for knowledge of the contingency between instrumental actions and their outcomes, nevertheless influences instrumental behaviour strongly by allowing Pavlovian CSs to affect the level of instrumental responding (Pavlovian-instrumental transfer), and is required for the normal ability of animals to choose rewards that are delayed. The prelimbic cortex is required for the detection of instrumental action-outcome contingencies, while insular cortex may allow rats to retrieve the values of specific foods via their sensory properties. The orbitofrontal cortex, like the BLA, may represent aspects of reinforcer value that govern instrumental choice behaviour. Finally, the anterior cingulate cortex, implicated in human disorders of emotion and attention, may have multiple roles in responding to the emotional significance of stimuli and to errors in performance, preventing responding to inappropriate stimuli. (C) 2002 Elsevier Science Ltd. All rights reserved.
    BibTeX:
    @article{Cardinal2002,
      author = {Cardinal, RN and Parkinson, JA and Hall, J and Everitt, BJ},
      title = {Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex},
      journal = {NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS},
      year = {2002},
      volume = {26},
      number = {3},
      pages = {321-352}
    }
    
    Cardinal, R., Pennicott, D., Sugathapala, C., Robbins, T. & Everitt, B. Impulsive choice induced in rats by lesions of the nucleus accumbens core {2001} SCIENCE
    Vol. {292}({5526}), pp. {2499-2501} 
    article  
    Abstract: Impulsive choice is exemplified by choosing a small or poor reward that is available immediately, in preference to a Larger but delayed reward. Impulsive choice contributes to drug addiction, attention-deficit/hyperactivity disorder, mania, and personality disorders, but its neuroanatomical basis is unclear. Here, we show that selective Lesions of the nucleus accumbens core induce persistent impulsive choice in rats. In contrast, damage to two of its afferents, the anterior cingulate cortex and medial prefrontal cortex, had no effect on this capacity. Thus, dysfunction of the nucleus accumbens core may be a key element in the neuropathology of impulsivity.
    BibTeX:
    @article{Cardinal2001,
      author = {Cardinal, RN and Pennicott, DR and Sugathapala, CL and Robbins, TW and Everitt, BJ},
      title = {Impulsive choice induced in rats by lesions of the nucleus accumbens core},
      journal = {SCIENCE},
      year = {2001},
      volume = {292},
      number = {5526},
      pages = {2499-2501}
    }
    
    Carlezon, W., Duman, R. & Nestler, E. The many faces of CREB {2005} TRENDS IN NEUROSCIENCES
    Vol. {28}({8}), pp. {436-445} 
    article DOI  
    Abstract: The transcription factor CREB is best known for its involvement in learning and memory. However, emerging evidence suggests that CREB activity has very different roles - sometimes beneficial, sometimes detrimental - depending on the brain region involved. Induction of CREB in the hippocampus by antidepressant treatments could contribute to their therapeutic efficacy. By contrast, activation of CREB in the nucleus accumbens and several other regions by drugs of abuse or stress mediates certain aspects of drug addiction, and depressive and anxiety-like behaviors. These complexities suggest that strategies that exploit regional differences in upstream factors or that target specific CREB-regulated genes, rather than CREB itself, could make a promising contribution to the treatment of neuropsychiatric conditions.
    BibTeX:
    @article{Carlezon2005,
      author = {Carlezon, WA and Duman, RS and Nestler, EJ},
      title = {The many faces of CREB},
      journal = {TRENDS IN NEUROSCIENCES},
      year = {2005},
      volume = {28},
      number = {8},
      pages = {436-445},
      doi = {{10.1016/j.tins.2005.06.005}}
    }
    
    Carlezon, W., Thome, J., Olson, V., Lane-Ladd, S., Brodkin, E., Hiroi, N., Duman, R., Neve, R. & Nestler, E. Regulation of cocaine reward by CREB {1998} SCIENCE
    Vol. {282}({5397}), pp. {2272-2275} 
    article  
    Abstract: Cocaine regulates the transcription factor CREB (adenosine 3',5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes Low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin Likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa opioid receptors ton which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade-culminating in gene expression-through which exposure to cocaine modifies subsequent responsiveness to the drug.
    BibTeX:
    @article{Carlezon1998,
      author = {Carlezon, WA and Thome, J and Olson, VG and Lane-Ladd, SB and Brodkin, ES and Hiroi, N and Duman, RS and Neve, RL and Nestler, EJ},
      title = {Regulation of cocaine reward by CREB},
      journal = {SCIENCE},
      year = {1998},
      volume = {282},
      number = {5397},
      pages = {2272-2275}
    }
    
    Carlezon, W. & Wise, R. Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex {1996} JOURNAL OF NEUROSCIENCE
    Vol. {16}({9}), pp. {3112-3122} 
    article  
    Abstract: Rats learned to lever-press when such behavior was reinforced by microinjections of phencyclidine (PCP) directly into the ventromedial (shell) region of nucleus accumbens, indicating that the drug has direct rewarding actions in that region. Separate groups of rats learned to lever-press when reinforced with microinjections of dizocilpine (MK-801) or 3-((+/-)2-carboxypiperazin-4yl)propyl-1-phosphate (CPP), drugs known to block NMDA receptor function but not dopamine uptake, into the same region. Each drug was ineffective or markedly less effective when injected at a slightly more dorsal and lateral site in the core of nucleus accumbens. Self-administration of PCP, MK-801, or CPP directly into nucleus accumbens was not altered by co-infusion of a dose of the dopamine antagonist sulpiride that effectively blocked intracranial self-administration of the dopamine uptake inhibitor nomifensine, suggesting that the rewarding actions of the NMDA receptor antagonists are not dopamine-dependent. Rats also developed lever-pressing habits when PCP, MK-801, and CPP were each microinjected directly into frontal cortex, a region previously associated with the rewarding actions of cocaine but not nomifensine. Thus nucleus accumbens and frontal cortex are each potential substrates for the rewarding properties of PCP and related drugs, and the ability of these drugs to disrupt NMDA receptor function seems sufficient to account for their rewarding actions. When considered with independent evidence, the present results suggest a model of drug reward within which the critical event is inhibition of medium spiny neurons in nucleus accumbens.
    BibTeX:
    @article{Carlezon1996,
      author = {Carlezon, WA and Wise, RA},
      title = {Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1996},
      volume = {16},
      number = {9},
      pages = {3112-3122}
    }
    
    Carr, D. & Sesack, S. Projections from the rat prefrontal cortex to the ventral tegmental area: Target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons {2000} JOURNAL OF NEUROSCIENCE
    Vol. {20}({10}), pp. {3864-3873} 
    article  
    Abstract: Excitatory projections from the prefrontal cortex (PFC) to the ventral tegmental area (VTA) play an important role in regulating the activity of VTA neurons and the extracellular levels of dopamine (DA) within forebrain regions. Previous investigations have demonstrated that PFC terminals synapse on the dendrites of DA and non-DA neurons in the VTA. However, the projection targets of these cells are not known. To address whether PFC afferents innervate different populations of VTA neurons that project to the nucleus accumbens (NAc) or to the PFC, a triple labeling method was used that combined peroxidase markers for anterograde and retrograde tract-tracing with pre-embedding immunogold-silver labeling for either tyrosine hydroxylase (TH) or GABA. Within the VTA, PFC terminals formed asymmetric synapses onto dendritic shafts that were immunoreactive for either TH or GABA. PFC terminals also synapsed on VTA dendrites that were retrogradely labeled from the NAc or the PFC. Dendrites retrogradely labeled from the NAc and postsynaptic to PFC afferents were sometimes immunoreactive for GABA but were never TH-labeled. Conversely, dendrites retrogradely labeled from the PFC and postsynaptic to PFC afferents were sometimes immunoreactive for TH but were never GABA-labeled. These results provide the first demonstration of PFC afferents synapsing on identified cell populations in the VTA and indicate a considerable degree of specificity in the targets of the PFC projection. The unexpected finding of selective PFC synaptic input to GABA-containing mesoaccumbens neurons and DA-containing mesocortical neurons suggests novel mechanisms through which the PFC can influence the activity of ascending DA and GABA projections.
    BibTeX:
    @article{Carr2000,
      author = {Carr, DB and Sesack, SR},
      title = {Projections from the rat prefrontal cortex to the ventral tegmental area: Target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2000},
      volume = {20},
      number = {10},
      pages = {3864-3873}
    }
    
    CARROLL, F., LEWIN, A., BOJA, J. & KUHAR, M. COCAINE RECEPTOR - BIOCHEMICAL-CHARACTERIZATION AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF COCAINE ANALOGS AT THE DOPAMINE TRANSPORTER {1992} JOURNAL OF MEDICINAL CHEMISTRY
    Vol. {35}({6}), pp. {969-981} 
    article  
    BibTeX:
    @article{CARROLL1992,
      author = {CARROLL, FI and LEWIN, AH and BOJA, JW and KUHAR, MJ},
      title = {COCAINE RECEPTOR - BIOCHEMICAL-CHARACTERIZATION AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF COCAINE ANALOGS AT THE DOPAMINE TRANSPORTER},
      journal = {JOURNAL OF MEDICINAL CHEMISTRY},
      year = {1992},
      volume = {35},
      number = {6},
      pages = {969-981}
    }
    
    Cartmell, J. & Schoepp, D. Regulation of neurotransmitter release by metabotropic glutamate receptors {2000} JOURNAL OF NEUROCHEMISTRY
    Vol. {75}({3}), pp. {889-907} 
    article  
    Abstract: The G protein-coupled metabotropic glutamate (mGlu) receptors are differentially localized at various synapses throughout the brain. Depending on the receptor subtype, they appear to be localized at presynaptic and/or postsynaptic sites, including glial as well as neuronal elements. The heterogeneous distribution of these receptors on glutamate and nonglutamate neurons/cells thus allows modulation of synaptic transmission by a number of different mechanisms, Electrophysiological studies have demonstrated that the activation of mGlu receptors can modulate the activity of Ca2+ or K+ channels, or interfere with release processes downstream of Ca2+ entry, and consequently regulate neuronal synaptic activity. Such changes evoked by mGlu receptors can ultimately regulate transmitter release at both glutamatergic and nonglulamatergic synapses, Increasing neurochemical evidence has emerged, obtained from in vitro and in vivo studies, showing modulation of the release of a variety of transmitters by mGlu receptors, This review addresses the neurochemical evidence for mGlu receptor-mediated regulation of neurotransmitters, such as excitatory and inhibitory amino acids, monoamines, and neuropeptides.
    BibTeX:
    @article{Cartmell2000,
      author = {Cartmell, J and Schoepp, DD},
      title = {Regulation of neurotransmitter release by metabotropic glutamate receptors},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {2000},
      volume = {75},
      number = {3},
      pages = {889-907}
    }
    
    Cepeda, C., Colwell, C., Itri, J., Chandler, S. & Levine, M. Dopaminergic modulation of NMDA-induced whole cell currents in neostriatal neurons in slices: Contribution of calcium conductances {1998} JOURNAL OF NEUROPHYSIOLOGY
    Vol. {79}({1}), pp. {82-94} 
    article  
    Abstract: The present experiments were designed to examine dopamine (DA) modulation of whole cell currents mediated by activation of N-methyl-D-aspartate (NMDA) receptors in visualized neostriatal neurons in slices. First, we assessed the ability of DA, D-1 and D-2 receptor agonists to modulate membrane currents induced by activation of NMDA receptors. The results of these experiments demonstrated that DA potentiated NMDA-induced currents in medium-sized neostriatal neurons. Potentiation of NMDA currents occurred at three different holding potentials, although it was more pronounced at -30 mV. It was mediated by D-1 receptors, because it was mimicked by D-1 agonists and blocked by exposure to a D-2 antagonist. Activation of D-2 receptors produced inconsistent effects on NMDA-induced membrane currents. Either decreases, increases, or no effects on NMDA currents occurred. Second, vie examined the contributions of intrinsic, voltage-dependent conductances to DA potentiation of NMDA currents. Blockade of K+ conductances did not prevent DA enhancement of NMDA currents. However, voltage-activated Ca2+ conductances provided a major contribution to DA modulation. The dihydropyridine L-type Ca2+ channel blockers, nifedipine, and methoxyverapamil (D-600), markedly reduced but did not totally eliminate the ability of DA to modulate NMDA currents. The D-1 receptor agonist SKF 38393 also enhanced Ba2+ currents in neostriatal neurons. Together, these findings provide evidence for a complex interplay between DA, NMDA receptor activation and dihydropyridine-sensitive Ca2+ conductances in controlling responsiveness of neostriatal medium-sized neurons.
    BibTeX:
    @article{Cepeda1998,
      author = {Cepeda, C and Colwell, CS and Itri, JN and Chandler, SH and Levine, MS},
      title = {Dopaminergic modulation of NMDA-induced whole cell currents in neostriatal neurons in slices: Contribution of calcium conductances},
      journal = {JOURNAL OF NEUROPHYSIOLOGY},
      year = {1998},
      volume = {79},
      number = {1},
      pages = {82-94}
    }
    
    Chambers, R., Taylor, J. & Potenza, M. Developmental neurocircuitry of motivation in adolescence: A critical period of addiction vulnerability {2003} AMERICAN JOURNAL OF PSYCHIATRY
    Vol. {160}({6}), pp. {1041-1052} 
    article  
    Abstract: Objective: Epidemiological studies indicate that experimentation with addictive drugs and onset of addictive disorders is primarily concentrated in adolescence and young adulthood. The authors describe basic and clinical data supporting adolescent neurodevelopment as a biologically critical period of greater vulnerability for experimentation with substances and acquisition of substance use disorders. Method: The authors reviewed recent literature regarding neurocircuitry underlying motivation, impulsivity, and addiction, with a focus on studies investigating adolescent neurodevelopment. Results: Adolescent neurodevelopment occurs in brain regions associated with motivation, impulsivity, and addiction. Adolescent impulsivity and/or novelty seeking as a transitional trait behavior can be explained in part by maturational changes in frontal cortical and subcortical monoaminergic systems. These developmental processes may advantageously promote learning drives for adaptation to adult roles but may also confer greater vulnerability to the addictive actions of drugs. Conclusions: An exploration of developmental changes in neurocircuitry involved in impulse control has significant implications for understanding adolescent behavior, addiction vulnerability, and the prevention of addiction in adolescence and adulthood.
    BibTeX:
    @article{Chambers2003,
      author = {Chambers, RA and Taylor, JR and Potenza, MN},
      title = {Developmental neurocircuitry of motivation in adolescence: A critical period of addiction vulnerability},
      journal = {AMERICAN JOURNAL OF PSYCHIATRY},
      year = {2003},
      volume = {160},
      number = {6},
      pages = {1041-1052}
    }
    
    Champtiaux, N., Gotti, C., Cordero-Erausquin, M., David, D., Przybylski, C., Lena, C., Clementi, F., Moretti, M., Rossi, F., Le Novere, N., McIntosh, J., Gardier, A. & Changeux, J. Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice {2003} JOURNAL OF NEUROSCIENCE
    Vol. {23}({21}), pp. {7820-7829} 
    article  
    Abstract: Nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic (DA) neurons have long been considered as potential therapeutic targets for the treatment of several neuropsychiatric diseases, including nicotine and cocaine addiction or Parkinson's disease. However, DA neurons express mRNAs coding for most, if not all, neuronal nAChR subunits, and the subunit composition of functional nAChRs has been difficult to establish. Immunoprecipitation experiments performed on mouse striatal extracts allowed us to identify three main types of heteromeric nAChRs (alpha4beta2(star), alpha6beta2(star), and alpha4alpha6beta2(star)) in DA terminal fields. The functional relevance of these subtypes was then examined by studying nicotine-induced DA release in striatal synaptosomes and recording ACh-elicited currents in DA neurons from alpha4, alpha6, alpha4alpha6, and beta2 knock-out mice. Our results establish that alpha6beta2(star) nAChRs are functional and sensitive to alpha-conotoxin MII inhibition. These receptors are mainly located on DA terminals and consistently do not contribute to DA release induced by systemic nicotine administration, as evidenced by in vivo microdialysis. In contrast, (nonalpha6)alpha4beta2(star) nAChRs represent the majority of functional heteromeric nAChRs on DA neuronal soma. Thus, whereas a combination of alpha6beta2(star) and alpha4beta2(star) nAChRs may mediate the endogenous cholinergic modulation of DA release at the terminal level, somato-dendritic (nonalpha6)alpha4beta2(star) nAChRs most likely contribute to nicotine reinforcement.
    BibTeX:
    @article{Champtiaux2003,
      author = {Champtiaux, N and Gotti, C and Cordero-Erausquin, M and David, DJ and Przybylski, C and Lena, C and Clementi, F and Moretti, M and Rossi, FM and Le Novere, N and McIntosh, JM and Gardier, AM and Changeux, JP},
      title = {Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2003},
      volume = {23},
      number = {21},
      pages = {7820-7829}
    }
    
    CharriautMarlangue, C., Margaill, I., Represa, A., Popovici, T., Plotkine, M. & BenAri, Y. Apoptosis and necrosis after reversible focal ischemia: An in situ DNA fragmentation analysis {1996} JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
    Vol. {16}({2}), pp. {186-194} 
    article  
    Abstract: Apoptosis is one of the two forms of cell death and occurs under a variety of physiological and pathological conditions. Cells undergoing apoptotic cell death reveal a characteristic sequence of cytological alterations including membrane blebbing and nuclear and cytoplasmic condensation. Early activation of an endonuclease has been previously demonstrated after a transient focal ischemia in the rat brain (Charriaut-Marlangue C, Margaill I, Plotkine M, Ben-Ari Y (1995) Early endonuclease activation following reversible focal ischemia. J Cereb Blood Flow Metab 15:385-388). We now show that a significant number of striatal and cortical neurons exhibited chromatin condensation, nucleus segmentation, and apoptotic bodies increasing with recirculation time, as demonstrated by in situ labeling of DNA breaks in cryostat sections. Apoptotic nuclei were also detected in the horizontal limb diagonal band, accumbens nucleus and islands of Calleja. Several necrotic neurons, in which random DNA fragmentation occurs, were also shown at 6 h recirculation, in the ischemic core. Further investigation with hematoxylin/eosin staining revealed that apoptotic nuclei were present in cells with a large and swelled cy toplasm and in cells with an apparently well-preserved cytoplasm. These two types of cell death were reminiscent of those described in developmental cell death. Our data suggested that apoptosis may contribute to the expansion of the ischemic lesion.
    BibTeX:
    @article{CharriautMarlangue1996,
      author = {CharriautMarlangue, C and Margaill, I and Represa, A and Popovici, T and Plotkine, M and BenAri, Y},
      title = {Apoptosis and necrosis after reversible focal ischemia: An in situ DNA fragmentation analysis},
      journal = {JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM},
      year = {1996},
      volume = {16},
      number = {2},
      pages = {186-194}
    }
    
    CHEN, J., PAREDES, W., LI, J., SMITH, D., LOWINSON, J. & GARDNER, E. DELTA-9-TETRAHYDROCANNABINOL PRODUCES NALOXONE-BLOCKABLE ENHANCEMENT OF PRESYNAPTIC BASAL DOPAMINE EFFLUX IN NUCLEUS-ACCUMBENS OF CONSCIOUS, FREELY-MOVING RATS AS MEASURED BY INTRACEREBRAL MICRODIALYSIS {1990} PSYCHOPHARMACOLOGY
    Vol. {102}({2}), pp. {156-162} 
    article  
    BibTeX:
    @article{CHEN1990,
      author = {CHEN, JP and PAREDES, W and LI, J and SMITH, D and LOWINSON, J and GARDNER, EL},
      title = {DELTA-9-TETRAHYDROCANNABINOL PRODUCES NALOXONE-BLOCKABLE ENHANCEMENT OF PRESYNAPTIC BASAL DOPAMINE EFFLUX IN NUCLEUS-ACCUMBENS OF CONSCIOUS, FREELY-MOVING RATS AS MEASURED BY INTRACEREBRAL MICRODIALYSIS},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1990},
      volume = {102},
      number = {2},
      pages = {156-162}
    }
    
    CHEN, J., VANPRAAG, H. & GARDNER, E. ACTIVATION OF 5-HT3 RECEPTOR BY 1-PHENYLBIGUANIDE INCREASES DOPAMINE RELEASE IN THE RAT NUCLEUS-ACCUMBENS {1991} BRAIN RESEARCH
    Vol. {543}({2}), pp. {354-357} 
    article  
    Abstract: The serotonin-3 (5-HT3) agonist 1-phenylbiguanide (0.1-1.0 mM in perfusate) caused a robust, dose-dependent enhancement of extracellular dopamine content in nucleus accumbens as measured by in vivo microdialysis. This action was antagonized by co-perfusion of the 5-HT3 antagonists zacopride and GR38032F (1 mM in perfusate). Similar effects were observed in 5-HT-denervated rats. These findings suggest that there is a potent modulation of dopamine (DA) release in the nucleus accumbens mediated via 5-HT3 receptors, which appear to be located presynaptically on DA terminals of the mesolimbic DA pathway.
    BibTeX:
    @article{CHEN1991,
      author = {CHEN, J and VANPRAAG, HM and GARDNER, EL},
      title = {ACTIVATION OF 5-HT3 RECEPTOR BY 1-PHENYLBIGUANIDE INCREASES DOPAMINE RELEASE IN THE RAT NUCLEUS-ACCUMBENS},
      journal = {BRAIN RESEARCH},
      year = {1991},
      volume = {543},
      number = {2},
      pages = {354-357}
    }
    
    Chiamulera, C., Epping-Jordan, M., Zocchi, A., Marcon, C., Cottiny, C., Tacconi, S., Corsi, M., Orzi, F. & Conquet, F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice {2001} NATURE NEUROSCIENCE
    Vol. {4}({9}), pp. {873-874} 
    article  
    BibTeX:
    @article{Chiamulera2001,
      author = {Chiamulera, C and Epping-Jordan, MP and Zocchi, A and Marcon, C and Cottiny, C and Tacconi, S and Corsi, M and Orzi, F and Conquet, F},
      title = {Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice},
      journal = {NATURE NEUROSCIENCE},
      year = {2001},
      volume = {4},
      number = {9},
      pages = {873-874}
    }
    
    CHRISTIE, M., SUMMERS, R., STEPHENSON, J., COOK, C. & BEART, P. EXCITATORY AMINO-ACID PROJECTIONS TO THE NUCLEUS-ACCUMBENS-SEPTI IN THE RAT - A RETROGRADE TRANSPORT STUDY UTILIZING D[H-3] ASPARTATE AND [H-3] GABA {1987} NEUROSCIENCE
    Vol. {22}({2}), pp. {425-439} 
    article  
    BibTeX:
    @article{CHRISTIE1987,
      author = {CHRISTIE, MJ and SUMMERS, RJ and STEPHENSON, JA and COOK, CJ and BEART, PM},
      title = {EXCITATORY AMINO-ACID PROJECTIONS TO THE NUCLEUS-ACCUMBENS-SEPTI IN THE RAT - A RETROGRADE TRANSPORT STUDY UTILIZING D[H-3] ASPARTATE AND [H-3] GABA},
      journal = {NEUROSCIENCE},
      year = {1987},
      volume = {22},
      number = {2},
      pages = {425-439}
    }
    
    CLIFFER, K., BURSTEIN, R. & GIESLER, G. DISTRIBUTIONS OF SPINOTHALAMIC, SPINOHYPOTHALAMIC, AND SPINOTELENCEPHALIC FIBERS REVEALED BY ANTEROGRADE TRANSPORT OF PHA-L IN RATS {1991} JOURNAL OF NEUROSCIENCE
    Vol. {11}({3}), pp. {852-868} 
    article  
    Abstract: Fibers projecting from several levels of the spinal cord to the diencephalon and telencephalon were labeled anterogradely with Phaseolus vulgaris leucoagglutinin injected iontophoretically. Labeled fibers in the thalamus confirmed projections previously observed. In addition, many labeled fibers were seen in the hypothalamus and in telencephalic areas not generally recognized previously as receiving such projections. In the hypothalamus, these areas included the lateral hypothalamus (including the medial forebrain bundle), the posterior hypothalamic area, the dorsal hypothalamic area, the dorsomedial nucleus, the paraventricular nucleus, the periventricular area, the suprachiasmatic nucleus, and the lateral and medial preoptic areas. In the telencephalon, areas with labeled fibers included the ventral pallidum, the globus pallidus, the substantia innominata, the basal nucleus of Meynert, the amygdala (central nucleus), the horizontal and vertical limbs of the diagonal band of Broca, the medial and lateral septal nuclei, the bed nucleus of the stria terminalis, the nucleus accumbens, infralimbic cortex, and medial orbital cortex. These results suggest that somatosensory, possibly including visceral sensory, information is carried directly from the spinal cord to areas in the brain involved in autonomic regulation, motivation, emotion, attention, arousal, learning, memory, and sensory-motor integration. Many of these areas are associated with the limbic system.
    BibTeX:
    @article{CLIFFER1991,
      author = {CLIFFER, KD and BURSTEIN, R and GIESLER, GJ},
      title = {DISTRIBUTIONS OF SPINOTHALAMIC, SPINOHYPOTHALAMIC, AND SPINOTELENCEPHALIC FIBERS REVEALED BY ANTEROGRADE TRANSPORT OF PHA-L IN RATS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1991},
      volume = {11},
      number = {3},
      pages = {852-868}
    }
    
    COLE, R., KONRADI, C., DOUGLASS, J. & HYMAN, S. NEURONAL ADAPTATION TO AMPHETAMINE AND DOPAMINE - MOLECULAR MECHANISMS OF PRODYNORPHIN GENE-REGULATION IN RAT STRIATUM {1995} NEURON
    Vol. {14}({4}), pp. {813-823} 
    article  
    Abstract: Induction of prodynorphin gene expression by psychostimulant drugs may re present a compensatory adaptation to excessive dopamine stimulation and may contribute to the aversive aspects of withdrawal. We therefore investigated the molecular mechanisms by which dopamine psychostimulant drugs induce prodynorphin gene expression in vivo and in rat primary striatal cultures. We demonstrate that three recently described cAMP response elements (CREs), rather than a previously reported noncanonical AP-1 site, are critical for dopamine induction of the prodynorphin gene in striatal neurons. CRE-binding protein (CREB) binds to these CREs in striatal cell extracts and is phosphorylated on Ser-133 after dopamine stimulation in a D1 dopamine receptor-dependent manner. Surprisingly, following chronic administration of amphetamine, revels of phosphorylated CREB are increased above basal in rat striatum in vivo, whereas c-fos mRNA is suppressed below basal levels. D1 receptor-mediated CREB phosphorylation appears to mediate adaptations to psychostimulant drugs in the striatum.
    BibTeX:
    @article{COLE1995,
      author = {COLE, RL and KONRADI, C and DOUGLASS, J and HYMAN, SE},
      title = {NEURONAL ADAPTATION TO AMPHETAMINE AND DOPAMINE - MOLECULAR MECHANISMS OF PRODYNORPHIN GENE-REGULATION IN RAT STRIATUM},
      journal = {NEURON},
      year = {1995},
      volume = {14},
      number = {4},
      pages = {813-823}
    }
    
    Cools, R., Clark, L., Owen, A. & Robbins, T. Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging {2002} JOURNAL OF NEUROSCIENCE
    Vol. {22}({11}), pp. {4563-4567} 
    article  
    Abstract: Event-related functional magnetic resonance imaging was used to measure blood oxygenation level-dependent responses in 13 young healthy human volunteers during performance of a probabilistic reversal-learning task. The task allowed the separate investigation of the relearning of stimulus-reward associations and the reception of negative feedback. Significant signal change in the right ventrolateral prefrontal cortex was demonstrated on trials when subjects stopped responding to the previously relevant stimulus and shifted responding to the newly relevant stimulus. Significant signal change in the region of the ventral striatum was also observed on such reversal errors, from a region of interest analysis. The ventrolateral prefrontal cortex and ventral striatum were not significantly activated by the other, preceding reversal errors, or when subjects received negative feedback for correct responses. Moreover, the response on the final reversal error, before shifting, was not modulated by the number of preceding reversal errors, indicating that error-related activity does not simply accumulate in this network. The signal change in this ventral frontostriatal circuit is therefore associated with reversal learning and is uncontaminated by negative feedback. Overall, these data concur with findings in rodents and nonhuman primates of reversal-learning deficits after damage to ventral frontostriatal circuitry, and also support recent clinical findings using this task.
    BibTeX:
    @article{Cools2002,
      author = {Cools, R and Clark, L and Owen, AM and Robbins, TW},
      title = {Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2002},
      volume = {22},
      number = {11},
      pages = {4563-4567}
    }
    
    CORBETT, R., CAMACHO, F., WOODS, A., KERMAN, L., FISHKIN, R., BROOKS, K. & DUNN, R. ANTIPSYCHOTIC AGENTS ANTAGONIZE NONCOMPETITIVE N-METHYL-D-ASPARTATE ANTAGONIST-INDUCED BEHAVIORS {1995} PSYCHOPHARMACOLOGY
    Vol. {120}({1}), pp. {67-74} 
    article  
    Abstract: Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.
    BibTeX:
    @article{CORBETT1995,
      author = {CORBETT, R and CAMACHO, F and WOODS, AT and KERMAN, LL and FISHKIN, RJ and BROOKS, K and DUNN, RW},
      title = {ANTIPSYCHOTIC AGENTS ANTAGONIZE NONCOMPETITIVE N-METHYL-D-ASPARTATE ANTAGONIST-INDUCED BEHAVIORS},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1995},
      volume = {120},
      number = {1},
      pages = {67-74}
    }
    
    Cordero-Erausquin, M., Marubio, L., Klink, R. & Changeux, J. Nicotinic receptor function: new perspectives from knockout mice {2000} TRENDS IN PHARMACOLOGICAL SCIENCES
    Vol. {21}({6}), pp. {211-217} 
    article  
    Abstract: Knockout mice, in which one or more genes of interest are silenced, provide unique opportunities to analyse diverse aspects of gene function in vivo. In particular, the contribution of the encoded protein(s) in complex behaviours can be assessed. Since the first targeted disruption in 1995 of the gene encoding the beta 2-subunit of the nicotinic acetylcholine receptor (nAChR), all but a few of the mammalian nAChR subunits have been disrupted (i.e, alpha 7, alpha 4, alpha 3, (alpha 9, beta 4 and beta 3). Recent advances brought by genetically modified mice to our understanding of the endogenous composition and role of nAChRs in the nervous system, and of the diverse pharmacological actions of nicotine regarding learning, analgesia, reinforcement, development and aging in the brain will be discussed.
    BibTeX:
    @article{Cordero-Erausquin2000,
      author = {Cordero-Erausquin, M and Marubio, LM and Klink, R and Changeux, JP},
      title = {Nicotinic receptor function: new perspectives from knockout mice},
      journal = {TRENDS IN PHARMACOLOGICAL SCIENCES},
      year = {2000},
      volume = {21},
      number = {6},
      pages = {211-217}
    }
    
    CORRIGALL, W., COEN, K. & ADAMSON, K. SELF-ADMINISTERED NICOTINE ACTIVATES THE MESOLIMBIC DOPAMINE SYSTEM THROUGH THE VENTRAL TEGMENTAL AREA {1994} BRAIN RESEARCH
    Vol. {653}({1-2}), pp. {278-284} 
    article  
    Abstract: Microinfusions of the nicotinic antagonist dihydro-beta-erythroidine (DH beta E) were used to examine the role of the mesolimbic dopamine system in nicotine reinforcement in rats. Infusions of DH beta E into the ventral tegmental area (VTA) prior to the start of i.v. nicotine self-administration sessions resulted in a significant decrease in the number of nicotine infusions voluntarily obtained. In contrast, the same doses of DH beta E infused into the nucleus accumbens were without effect on nicotine self-administration The reductions caused by DH beta E were specific to nicotine reinforcement; neither operant responding maintained by food, cocaine self-administration, or spontaneous locomotor activity were altered by local applications of DH beta E within the VTA. The reduction in nicotine self-administration following treatment in the VTA was also specific to the nicotinic antagonist, and was not duplicated by infusions of the muscarinic antagonist atropine. Partial lesions of the pedunculopontine tegmental nucleus, the likely origin of cholinergic fibers to the VTA, were without effect on nicotine self-administration, suggesting that the effects of DH beta E were not due to disruption of a tonically active cholinergic input to the VTA from this source. These data show that nicotine acts within the VTA region to initiate processes which are critical to the reinforcing properties of the drug.
    BibTeX:
    @article{CORRIGALL1994,
      author = {CORRIGALL, WA and COEN, KM and ADAMSON, KL},
      title = {SELF-ADMINISTERED NICOTINE ACTIVATES THE MESOLIMBIC DOPAMINE SYSTEM THROUGH THE VENTRAL TEGMENTAL AREA},
      journal = {BRAIN RESEARCH},
      year = {1994},
      volume = {653},
      number = {1-2},
      pages = {278-284}
    }
    
    CORRIGALL, W., FRANKLIN, K., COEN, K. & CLARKE, P. THE MESOLIMBIC DOPAMINERGIC SYSTEM IS IMPLICATED IN THE REINFORCING EFFECTS OF NICOTINE {1992} PSYCHOPHARMACOLOGY
    Vol. {107}({2-3}), pp. {285-289} 
    article  
    Abstract: Rats were trained to self-administer nicotine on a fixed-ratio schedule of reinforcement. Infusion of the nicotinic antagonist chlorisondamine into the cerebral ventricles produced a sustained reduction in nicotine self-administration compared to vehicle-treated controls. Lesions of the mesolimbic dopamine system were produced by microinfusion of 6-hydroxydopamine into the nucleus accumbens. Following production of the lesions, nicotine self-administration was markedly reduced for the 3-week test period; motor impairment did not appear to be responsible. Post mortem analysis of brain tissue showed that the lesion produced a pronounced decrease in dopamine content of the nucleus accumbens and the olfactory tubercle, and a small depletion in the striatum. These data demonstrate that the reinforcing effects of nicotine occur within the central nervous system, and that the mesolimbic dopamine projection plays an important role in these effects.
    BibTeX:
    @article{CORRIGALL1992,
      author = {CORRIGALL, WA and FRANKLIN, KBJ and COEN, KM and CLARKE, PBS},
      title = {THE MESOLIMBIC DOPAMINERGIC SYSTEM IS IMPLICATED IN THE REINFORCING EFFECTS OF NICOTINE},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1992},
      volume = {107},
      number = {2-3},
      pages = {285-289}
    }
    
    CRAWLEY, J. CHOLECYSTOKININ-DOPAMINE INTERACTIONS {1991} TRENDS IN PHARMACOLOGICAL SCIENCES
    Vol. {12}({6}), pp. {232-236} 
    article  
    Abstract: Cholecystokinin (CCK) coexists with dopamine in a large proportion of the ventral tegmental and substantia nigra neurons in rodents and primates. In this review Jacki Crawley integrates the neurophysiological, behavioral, and release studies which demonstrate both excitatory effects of CCK, and facilitatory modulating effects of CCK on the inhibitory actions of dopamine, in the mesolimbic pathway. Nonpeptide antagonists selective for the CCK(A) and CCK(B) receptors have recently been developed, and provide long-awaited tools to test hypotheses about the role of endogenous CCK as a modulator of dopaminergic function, and the potential of CCK-based drugs as treatments for neuropsychiatric disorders.
    BibTeX:
    @article{CRAWLEY1991,
      author = {CRAWLEY, JN},
      title = {CHOLECYSTOKININ-DOPAMINE INTERACTIONS},
      journal = {TRENDS IN PHARMACOLOGICAL SCIENCES},
      year = {1991},
      volume = {12},
      number = {6},
      pages = {232-236}
    }
    
    CRAWLEY, J. & CORWIN, R. BIOLOGICAL ACTIONS OF CHOLECYSTOKININ {1994} PEPTIDES
    Vol. {15}({4}), pp. {731-755} 
    article  
    BibTeX:
    @article{CRAWLEY1994,
      author = {CRAWLEY, JN and CORWIN, RL},
      title = {BIOLOGICAL ACTIONS OF CHOLECYSTOKININ},
      journal = {PEPTIDES},
      year = {1994},
      volume = {15},
      number = {4},
      pages = {731-755}
    }
    
    CUBELLS, J., RAYPORT, S., RAJENDRAN, G. & SULZER, D. METHAMPHETAMINE NEUROTOXICITY INVOLVES VACUOLATION OF ENDOCYTIC ORGANELLES AND DOPAMINE-DEPENDENT INTRACELLULAR OXIDATIVE STRESS {1994} JOURNAL OF NEUROSCIENCE
    Vol. {14}({4}), pp. {2260-2271} 
    article  
    Abstract: Methamphetamine (MA) produces selective degeneration of dopamine (DA) neuron terminals without cell body loss. While excitatory amino acids (EAAs) contribute to MA toxicity, terminal loss is not characteristic of excitotoxic lesions nor is excitotoxicity selective for DA fibers; rather, EAAs may modulate MA-induced DA turnover, suggesting that DA-dependent events play a key role in MA neurotoxicity. To examine this possibility, we used postnatal ventral midbrain DA neuron cultures maintained under continuous EAA blockade. As in vivo, MA caused neurite degeneration but minimal cell death. We found that MA is a vacuologenic weak base that induces swelling of endocytic compartments; MA also induces blebbing of the plasma membrane. However, these morphological changes occurred in MA-treated cultures lacking DA neurons. Therefore, while collapse of endosomal and lysosomal pH gradients and vacuolation may contribute to MA neurotoxicity, this does not explain selective DA terminal degeneration. Alternatively, MA could exert its neurotoxic effects by collapsing synaptic vesicle proton gradients and redistributing DA from synaptic vesicles to the cytoplasm. This could cause the formation of DA-derived free radicals and reactive metabolites. To test whether MA induces oxidative stress within living DA neurons, we used 2,7-dichlorofluorescin diacetate (DCF), an indicator of intracellular hydroperoxide production. MA dramatically increased the number of DCF-labeled cells in ventral midbrain cultures, which contain about 30% DA neurons, but not in nucleus accumbens cultures, which do not contain DA neurons. In the DA neuron cultures, intracellular DDF labeling was localized to axonal varicosities, blebs, and endocytic organelles. These results suggest that MA redistributes DA from the reducing environment within synaptic vesicles to extravesicular oxidizing environments, thus generating oxygen radicals and reactive metabolites within DA neurons that may trigger selective DA terminal loss.
    BibTeX:
    @article{CUBELLS1994,
      author = {CUBELLS, JF and RAYPORT, S and RAJENDRAN, G and SULZER, D},
      title = {METHAMPHETAMINE NEUROTOXICITY INVOLVES VACUOLATION OF ENDOCYTIC ORGANELLES AND DOPAMINE-DEPENDENT INTRACELLULAR OXIDATIVE STRESS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1994},
      volume = {14},
      number = {4},
      pages = {2260-2271}
    }
    
    Dalack, G., Healy, D. & Meador-Woodruff, J. Nicotine dependence in schizophrenia: Clinical phenomena and laboratory findings {1998} AMERICAN JOURNAL OF PSYCHIATRY
    Vol. {155}({11}), pp. {1490-1501} 
    article  
    Abstract: Objective: The goal of this report is to examine the potential implications of the high prevalence of smoking in schizophrenia for our understanding of this illness, Method: A selective review of the relevant clinical and preclinical literature was conducted. The authors present a review of the clinical observations about smoking in schizophrenia, summarize the preclinical data about the complexity of the CNS nicotinic receptor family, and examine the modulatory effects of nicotine on neurotransmitter systems implicated in schizophrenia, Results: Clinical data suggest that smoking in schizophrenia may represent an attempt to self-medicate symptoms of the illness. Preclinical findings support a potential role of nicotine in medicating negative symptoms in particular. Recent preclinical and clinical data suggest that schizophrenic patients have a primary defect in the CNS nicotinergic system that leads to abnormal sensory gating, The complexity of the neuromodulatory effects of CNS nicotinic systems on other neurotransmitter systems underscores both the scope and potential importance of continued advancement of research in this area, Conclusions: Despite increasing clinical research focused on the extremely high prevalence of smoking in schizophrenia, linkages to the prodigious preclinical data about nicotine and nicotinic receptors are largely unexplored. These linkages are likely to be very important, Integrating nicotine use into our clinical and basic models of schizophrenia leads to a more complex but more realistic representation of brain dysfunction in this illness. Understanding how and why schizophrenic individuals use nicotine may lead to the development of new treatments for both schizophrenia and nicotine dependence.
    BibTeX:
    @article{Dalack1998,
      author = {Dalack, GW and Healy, DJ and Meador-Woodruff, JH},
      title = {Nicotine dependence in schizophrenia: Clinical phenomena and laboratory findings},
      journal = {AMERICAN JOURNAL OF PSYCHIATRY},
      year = {1998},
      volume = {155},
      number = {11},
      pages = {1490-1501}
    }
    
    Dalley, J., Cardinal, R. & Robbins, T. Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates {2004} NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
    Vol. {28}({7}), pp. {771-784} 
    article DOI  
    Abstract: The prefrontal cortex has been implicated in a variety of cognitive and executive processes, including working memory, decision-making, inhibitory response control, attentional set-shifting and the temporal integration of voluntary behaviour. This article reviews current progress in our understanding of the rodent prefrontal cortex, especially evidence for functional divergence of the anatomically distinct sub-regions of the rat prefrontal cortex. Recent findings suggest clear distinctions between the dorsal (precentral and anterior cingulate) and ventral (prelimbic, infralimbic and medial orbital) sub-divisions of the medial prefrontal cortex, and between the orbitofrontal cortex (ventral orbital, ventrolateral orbital, dorsal and ventral agranular cortices) and the adjacent medial wall of the prefrontal cortex. The dorso-medial prefrontal cortex is implicated in memory for motor responses, including response selection, and the temporal processing of information. Ventral regions of the medial prefrontal cortex are implicated in interrelated `supervisory' attentional functions, including attention to stimulus features and task contingencies (or action-outcome rules), attentional set-shifting, and behavioural flexibility. The orbitofrontal cortex is implicated in lower-order discriminations, including reversal of stimulus-reward associations (reversal learning), and choice involving delayed reinforcement. It is anticipated that a greater understanding of the prefrontal cortex will come from using tasks that load specific cognitive and executive processes, in parallel with discovering new ways of manipulating the different sub-regions and neuromodulatory systems of the prefrontal cortex. (C) 2004 Elsevier Ltd. All rights reserved.
    BibTeX:
    @article{Dalley2004,
      author = {Dalley, JW and Cardinal, RN and Robbins, TW},
      title = {Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates},
      journal = {NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS},
      year = {2004},
      volume = {28},
      number = {7},
      pages = {771-784},
      doi = {{10.1016/j.neubiorev.2004.09.006}}
    }
    
    Dalley, J.W., Fryer, T.D., Brichard, L., Robinson, E.S.J., Theobald, D.E.H., Laeaene, K., Pena, Y., Murphy, E.R., Shah, Y., Probst, K., Abakumova, I., Aigbirhio, F.I., Richards, H.K., Hong, Y., Baron, J.-C., Everitt, B.J. & Robbins, T.W. Nucleus Accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement {2007} SCIENCE
    Vol. {315}({5816}), pp. {1267-1270} 
    article DOI  
    Abstract: Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.
    BibTeX:
    @article{Dalley2007,
      author = {Dalley, Jeffrey W. and Fryer, Tim D. and Brichard, Laurent and Robinson, Emma S. J. and Theobald, David E. H. and Laeaene, Kristjan and Pena, Yolanda and Murphy, Emily R. and Shah, Yasmene and Probst, Katrin and Abakumova, Irina and Aigbirhio, Franklin I. and Richards, Hugh K. and Hong, Young and Baron, Jean-Claude and Everitt, Barry J. and Robbins, Trevor W.},
      title = {Nucleus Accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement},
      journal = {SCIENCE},
      year = {2007},
      volume = {315},
      number = {5816},
      pages = {1267-1270},
      doi = {{10.1126/science.1137073}}
    }
    
    DAMSMA, G., WENKSTERN, D., PFAUS, J., PHILLIPS, A. & FIBIGER, H. SEXUAL-BEHAVIOR INCREASES DOPAMINE TRANSMISSION IN THE NUCLEUS-ACCUMBENS AND STRIATUM OF MALE-RATS - COMPARISON WITH NOVELTY AND LOCOMOTION {1992} BEHAVIORAL NEUROSCIENCE
    Vol. {106}({1}), pp. {181-191} 
    article  
    Abstract: Extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were examined concurrently, using in vivo microdialysis, in the nucleus accumbens and dorsal striatum of sexually active male rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually receptive female, and copulation. DA increased significantly in the nucleus accumbens when the males were presented with a sexually receptive female behind a screen and increased further during copulation. Although DA also increased significantly in the dorsal striatum during copulation, the magnitude of the effect was significantly lower than that observed in the nucleus accumbens. In contrast, forced locomotion on a rotating drum, exposure to a novel chamber, and exposure to sex odors did not increase DA significantly in either region, although both DOPAC and HVA increased significantly in both regions during the locomotion test. These results indicate that novelty or locomotor activity alone cannot account for the increased extracellular DA concentrations observed in the nucleus accumbens of male rats during the presentation of a sexually receptive female behind a screen, nor can they account for the increased DA concentrations observed in both the nucleus accumbens and dorsal striatum of male rats during copulation. The preferential increase in DA transmission in the nucleus accumbens, compared with that in the striatum, suggests that anticipatory and consummatory aspects of sexual activity may belong to a class of naturally occurring events with reward values that are mediated by DA release in the nucleus accumbens.
    BibTeX:
    @article{DAMSMA1992,
      author = {DAMSMA, G and WENKSTERN, D and PFAUS, JG and PHILLIPS, AG and FIBIGER, HC},
      title = {SEXUAL-BEHAVIOR INCREASES DOPAMINE TRANSMISSION IN THE NUCLEUS-ACCUMBENS AND STRIATUM OF MALE-RATS - COMPARISON WITH NOVELTY AND LOCOMOTION},
      journal = {BEHAVIORAL NEUROSCIENCE},
      year = {1992},
      volume = {106},
      number = {1},
      pages = {181-191}
    }
    
    Davidson, C., Gow, A., Lee, T. & Ellinwood, E. Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment {2001} BRAIN RESEARCH REVIEWS
    Vol. {36}({1}), pp. {1-22} 
    article  
    Abstract: Research into methamphetamine-induced neurotoxicity has experienced a resurgence in recent years. This is due to (1) greater understanding of the mechanisms underlying methamphetamine neurotoxicity, (2) its usefulness as a model for Parkinson's disease and (3) an increased abuse of the substance, especially in the American Mid-West and Japan. It is suggested that the commonly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are needed to accurately model human long-term abuse. Further, we suggest that these two dosing regimens will result in quite different neurochemical, neuropathological and behavioral outcomes. The relative importance of the dopamine transporter and vesicular monoamine transporter knockout is discussed and insights into oxidative mechanisms are described from observations of nNOS knockout and SOD overexpression. This review not only describes the neuropathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascades are also emphasized. Finally, we describe potential treatments for methamphetamine abusers with reference to the time after withdrawal. We suggest that potential treatments cart be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) amelioration of apoptotic cascades that may occur even in the withdrawal period and (3) treatment of the atypical depression associated with withdrawal. (C) 2001 Elsevier Science B.V All rights reserved.
    BibTeX:
    @article{Davidson2001,
      author = {Davidson, C and Gow, AJ and Lee, TH and Ellinwood, EH},
      title = {Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {2001},
      volume = {36},
      number = {1},
      pages = {1-22}
    }
    
    Dayan, P. & Balleine, B. Reward, motivation, and reinforcement learning {2002} NEURON
    Vol. {36}({2}), pp. {285-298} 
    article  
    Abstract: There is substantial evidence that dopamine is involved in reward learning and appetitive conditioning. However, the major reinforcement learning-based theoretical models of classical conditioning (crudely, prediction learning) are actually based on rules designed to explain instrumental conditioning (action learning). Extensive anatomical, pharmacological, and psychological data, particularly concerning the impact of motivational manipulations, show that these models are unreasonable. We review the data and consider the involvement of a rich collection of different neural systems in various aspects of these forms of conditioning. Dopamine plays a pivotal, but complicated, role.
    BibTeX:
    @article{Dayan2002,
      author = {Dayan, P and Balleine, BW},
      title = {Reward, motivation, and reinforcement learning},
      journal = {NEURON},
      year = {2002},
      volume = {36},
      number = {2},
      pages = {285-298}
    }
    
    De Vries, T., Schoffelmeer, A., Binnekade, R., Murder, A. & Vanderschuren, L. Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization {1998} EUROPEAN JOURNAL OF NEUROSCIENCE
    Vol. {10}({11}), pp. {3565-3571} 
    article  
    Abstract: The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 mu g/kg per inj., 14 daily sessions), cocaine (500 mu g/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on nonreinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.
    BibTeX:
    @article{DeVries1998,
      author = {De Vries, TJ and Schoffelmeer, ANM and Binnekade, R and Murder, AH and Vanderschuren, LJMJ},
      title = {Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization},
      journal = {EUROPEAN JOURNAL OF NEUROSCIENCE},
      year = {1998},
      volume = {10},
      number = {11},
      pages = {3565-3571}
    }
    
    De Vries, T., Shaham, Y., Homberg, J., Crombag, H., Schuurman, K., Dieben, J., Vanderschuren, L. & Schoffelmeer, A. A cannabinoid mechanism in relapse to cocaine seeking {2001} NATURE MEDICINE
    Vol. {7}({10}), pp. {1151-1154} 
    article  
    Abstract: Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine(1), by re-exposure to stimuli previously associated with cocaine(2) or by exposure to stress(3). In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods', thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction(7,8). The active ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system(9,10) and has rewarding effects in preclinical models of drug abuse(8,11,12). We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use.
    BibTeX:
    @article{DeVries2001,
      author = {De Vries, TJ and Shaham, Y and Homberg, JR and Crombag, H and Schuurman, K and Dieben, J and Vanderschuren, LJMJ and Schoffelmeer, ANM},
      title = {A cannabinoid mechanism in relapse to cocaine seeking},
      journal = {NATURE MEDICINE},
      year = {2001},
      volume = {7},
      number = {10},
      pages = {1151-1154}
    }
    
    DELFS, J., SCHREIBER, L. & KELLEY, A. MICROINJECTION OF COCAINE INTO THE NUCLEUS ACCUMBENS ELICITS LOCOMOTOR ACTIVATION IN THE RAT {1990} JOURNAL OF NEUROSCIENCE
    Vol. {10}({1}), pp. {303-310} 
    article  
    BibTeX:
    @article{DELFS1990,
      author = {DELFS, JM and SCHREIBER, L and KELLEY, AE},
      title = {MICROINJECTION OF COCAINE INTO THE NUCLEUS ACCUMBENS ELICITS LOCOMOTOR ACTIVATION IN THE RAT},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1990},
      volume = {10},
      number = {1},
      pages = {303-310}
    }
    
    Delfs, J., Zhu, Y., Druhan, J. & Aston-Jones, G. Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion {2000} NATURE
    Vol. {403}({6768}), pp. {430-434} 
    article  
    Abstract: Cessation of drug use in chronic opiate abusers produces a severe withdrawal syndrome that is highly aversive, and avoidance of withdrawal or associated stimuli is a major factor contributing to opiate abuse(1,2). Increased noradrenaline in the brain has long been implicated in opiate withdrawal(3), but it has not been clear which noradrenergic systems are invoked. Here we show that microinjection of beta-noradrenergic-receptor antagonists, or of an alpha 2-receptor agonist, into the bed nucleus of the stria terminalis (BNST) in rats markedly attenuates opiate-withdrawal-induced conditioned place aversion, Immunohistochemical studies revealed that numerous BNST-projecting cells in the A1 and A2 noradrenergic cell groups of the caudal medulla were activated during withdrawal Lesion of these ascending medullary projections also greatly reduced opiate-withdrawal-induced place aversion. whereas lesion of locus coeruleus noradrenergic projections had no effect on opiate-withdrawal behaviour. We conclude that noradrenergic inputs to the BNST from the caudal medulla are critically involved in the aversiveness of opiate withdrawal.
    BibTeX:
    @article{Delfs2000,
      author = {Delfs, JM and Zhu, Y and Druhan, JP and Aston-Jones, G},
      title = {Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion},
      journal = {NATURE},
      year = {2000},
      volume = {403},
      number = {6768},
      pages = {430-434}
    }
    
    Dellu, F., Piazza, P., Mayo, W., LeMoal, M. & Simon, H. Novelty-seeking in rats - Biobehavioral characteristics and possible relationship with the sensation-seeking trait in man {1996} NEUROPSYCHOBIOLOGY
    Vol. {34}({3}), pp. {136-145} 
    article  
    Abstract: A behavioral trait in rats which resembles some of the features of high-sensation seekers in man has been characterized. Given that the response to novelty is the basis of the definition of sensation-seeking, individual differences in reactivity to novelty have been studied on behavioral and biological levels. Certain individuals labeled as high responders (HR) as opposed to low responders (LR) have been shown to be highly reactive when exposed to a novel environment. These groups were investigated for free-choice responses to novel environments differing in complexity and aversiveness, and to other kinds of reinforcement, i.e. food and a drug, The HR rats appeared to seek novelty, variety and emotional stimulation. Only HR individuals have been found to be predisposed to drug-taking: they develop amphetamine self-administration whereas LR individuals do not. They also exhibit a higher sensitivity to the reinforcing properties of food. On a biological level, compared to LR rats, HR animals have an enhanced level of dopaminergic activity in the nucleus accumbens both under basal conditions or following a tail-pinch stress, HR and IR rats differ in reactivity of the corticotropic axis: HR rats exposed to a novel environment have a prolonged secretion of corticosterone compared to LR rats, The association of novelty, drug and food seeking in the same individual suggests that these characteristics share common processes. Differences in dopaminergic activity between IIR and LR rats are consistent with results implicating these dopaminergic neurons in response to novelty and in drug-taking behavior. Given that rats self-administer corticosterone and that HR rats are more sensitive to the reinforcing properties of corticosteroids, it could be speculated that HR rats seek novelty for the reinforcing action of corticosterone. These characteristics may be analogous to some for the features found in human high-sensation seekers and this animal model may be useful in determinating the biological basis of this human trait.
    BibTeX:
    @article{Dellu1996,
      author = {Dellu, F and Piazza, PV and Mayo, W and LeMoal, M and Simon, H},
      title = {Novelty-seeking in rats - Biobehavioral characteristics and possible relationship with the sensation-seeking trait in man},
      journal = {NEUROPSYCHOBIOLOGY},
      year = {1996},
      volume = {34},
      number = {3},
      pages = {136-145}
    }
    
    Depue, R. & Collins, P. Neurobiology of the structure of personality: Dopamine, facilitation of incentive motivation, and extraversion {1999} BEHAVIORAL AND BRAIN SCIENCES
    Vol. {22}({3}), pp. {491+} 
    article  
    Abstract: Extraversion has two central characteristics: (1) interpersonal engagement, which consists of affiliation (enjoying and valuing close interpersonal bonds, being warm and affectionate) and agency (being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals) and (2) impulsivity, which emerges from the interaction of extraversion and a second, independent trait (constraint). Agency is a more general motivational disposition that includes dominance, ambition, mastery, efficacy, and achievement. Positive affect (a combination of positive feelings and motivation) is closely associated with extraversion. Extraversion is accordingly based on positive incentive motivation. Parallels between extraversion (particularly its agency component) and a mammalian behavioral approach system based on positive incentive motivation implicate a neuroanatomical network and modulatory neurotransmitters in the processing of incentive motivation. A corticolimbic-striatal-thalamic network (1) integrates the salient incentive context in the medial orbital cortex, amygdala, and hippocampus; (2) encodes the intensity of incentive stimuli in a motive circuit composed of the nucleus accumbens, ventral pallidum, and ventral tegmental area dopamine projection system; and (3) creates an incentive motivational state that can be transmitted to the motor system. Individual differences in the functioning of this network arise from functional variation in the Ventral tegmental area dopamine projections, which are directly involved in coding the intensity of incentive motivation. The animal evidence suggests that there are three neurodevelopmental sources of individual differences in dopamine: genetic, ``experience-expectant,'' and ``experience-dependent.'' Individual differences in dopamine promote variation in the heterosynaptic plasticity that enhances the connection between incentive con text and incentive motivation and behavior. Our psychobiological threshold model explains the effects of individual differences in dopamine transmission on behavior, and their relation to personality traits is discussed.
    BibTeX:
    @article{Depue1999,
      author = {Depue, RA and Collins, PF},
      title = {Neurobiology of the structure of personality: Dopamine, facilitation of incentive motivation, and extraversion},
      journal = {BEHAVIORAL AND BRAIN SCIENCES},
      year = {1999},
      volume = {22},
      number = {3},
      pages = {491+}
    }
    
    Deroche-Gamonet, V., Belin, D. & Piazza, P. Evidence for addiction-like behavior in the rat {2004} SCIENCE
    Vol. {305}({5686}), pp. {1014-1017} 
    article  
    Abstract: Although the voluntary intake of drugs of abuse is a behavior largely preserved throughout phylogeny, it is currently unclear whether pathological drug use (''addiction'') can be observed in species other than humans. Here, we report that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine. As in humans, this addiction-like behavior is present only in a small proportion of subjects using cocaine and is highly predictive of relapse after withdrawal. These findings provide a new basis for developing a true understanding and treatment of addiction.
    BibTeX:
    @article{Deroche-Gamonet2004,
      author = {Deroche-Gamonet, V and Belin, D and Piazza, PV},
      title = {Evidence for addiction-like behavior in the rat},
      journal = {SCIENCE},
      year = {2004},
      volume = {305},
      number = {5686},
      pages = {1014-1017}
    }
    
    DEUTCH, A. & CAMERON, D. PHARMACOLOGICAL CHARACTERIZATION OF DOPAMINE SYSTEMS IN THE NUCLEUS-ACCUMBENS CORE AND SHELL {1992} NEUROSCIENCE
    Vol. {46}({1}), pp. {49-56} 
    article  
    Abstract: Recent anatomical data suggest that the nucleus accumbens can be parcellated into a core region, related to the caudate-putamen, and a shell region, associated with the limbic system. We have used pharmacological methods to characterize the dopamine innervations of the nucleus accumbens core and shell in the rat. Concentrations of both dopamine and serotonin were significantly greater in the nucleus accumbens shell than the nucleus accumbens core. Metabolite: amine ratios suggested that both dopamine and serotonin utilization are greater in the core. However, dopamine turnover (as determined by measuring the rate of decline of dopamine after alpha-methyl-p-tyrosine treatment) was not significantly different in the two accumbal sectors. Dopamine concentrations in the two nucleus accumbens sectors were decreased to an equivalent degree at both 4 and 18 h after reserpine administration. In contrast, serotonin concentrations were decreased to a significantly greater degree in the nucleus accumbens core than nucleus accumbens shell at 4 h, but not 18 h, after reserpine administration. Administration of haloperidol increased dopamine utilization in both nucleus accumbens sectors, but augmented utilization to a significantly greater degree in the nucleus accumbens core. Clozapine increased dopamine utilization to an equivalent degree in both nucleus accumbens regions. Short duration immobilization stress selectively increased dopamine utilization in the nucleus accumbens shell. These data indicate that there are significant differences between the nucleus accumbens core and nucleus accumbens shell in basal dopamine metabolism, and indicate that the core and shell dopamine innervations can be distinguished on the basis of response to both pharmacological and environmental challenges. These data are consistent with the hypothesis that the dopaminergic innervation of the nucleus accumbens core is associated with the nigrostriatal system, while that of the nucleus accumbens shell is related to the mesolimbic system.
    BibTeX:
    @article{DEUTCH1992,
      author = {DEUTCH, AY and CAMERON, DS},
      title = {PHARMACOLOGICAL CHARACTERIZATION OF DOPAMINE SYSTEMS IN THE NUCLEUS-ACCUMBENS CORE AND SHELL},
      journal = {NEUROSCIENCE},
      year = {1992},
      volume = {46},
      number = {1},
      pages = {49-56}
    }
    
    DEUTCH, A., LEE, M. & IADAROLA, M. REGIONALLY SPECIFIC EFFECTS OF ATYPICAL ANTIPSYCHOTIC-DRUGS ON STRIATAL FOS EXPRESSION - THE NUCLEUS-ACCUMBENS SHELL AS A LOCUS OF ANTIPSYCHOTIC ACTION {1992} MOLECULAR AND CELLULAR NEUROSCIENCE
    Vol. {3}({4}), pp. {332-341} 
    article  
    BibTeX:
    @article{DEUTCH1992a,
      author = {DEUTCH, AY and LEE, MC and IADAROLA, MJ},
      title = {REGIONALLY SPECIFIC EFFECTS OF ATYPICAL ANTIPSYCHOTIC-DRUGS ON STRIATAL FOS EXPRESSION - THE NUCLEUS-ACCUMBENS SHELL AS A LOCUS OF ANTIPSYCHOTIC ACTION},
      journal = {MOLECULAR AND CELLULAR NEUROSCIENCE},
      year = {1992},
      volume = {3},
      number = {4},
      pages = {332-341}
    }
    
    DEVINE, D., LEONE, P., POCOCK, D. & WISE, R. DIFFERENTIAL INVOLVEMENT OF VENTRAL TEGMENTAL-MU, TEGMENTAL-DELTA AND KAPPA-OPIOID RECEPTORS IN MODULATION OF BASAL MESOLIMBIC DOPAMINE RELEASE - IN-VIVO MICRODIALYSIS STUDIES {1993} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {266}({3}), pp. {1236-1246} 
    article  
    Abstract: In vivo microdialysis was used to assess the involvement of ventral tegmental area (VTA) mu, delta, and kappa opioid receptors in modulation of basal extracellular ventral striatal dopamine (DA) and DA-metabolite concentrations. Independent groups of chloral hydrate-anesthetized rats were given VTA microinjections of selective opioid agonists, and extracellular ventral striatal DA and DA-metabolite concentrations were assayed using HPLC. VTA microinjections of [D-Ala2, N-Me-Phe4-Gly5-ol]-enkephalin (DAMGO; a mu agonist) and [D-Pen2, D-Pen5]-enkephalin (DDDPE; a delta agonist) each caused dose-orderly increases in ventral striatal DA and DA-metabolite concentrations. The effective concentrations of DPDPE were 100- to 1000-fold higher than the effective concentrations of DAMGO. VTA microinjections of (trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidi-nyl)cyclo-hexyl]-b enzeneacetamide) methane sulfonate hydrate (U-50,488H); a kappa agonist) failed to alter ventral striatal DA concentrations at any dose tested, but subsequent systemic injections significantly decreased DA and DA-metabolite concentrations. Pretreatment with VTA microinjections of 17-cyclopropylmethyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'-indo lmorphinan hydrochloride (naltrindole; a delta antagonist) (delta antagonist) antagonized VTA DPDPE-mediated increases in ventral striatal DA and DA-metabolite concentrations but failed to antagonize VTA DAMGO-mediated increases. Pretreatment with D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; a mu antagonist) antagonized VTA DAMGO-mediated increases but failed to antagonize VTA DPDPE-mediated increases. Thus both mu and delta receptor agonists appear capable of increasing ventral striatal DA and DA-metabolite concentrations through selective actions on their preferred class of opioid receptors in the VTA. The increases in ventral striatal DA and DA-metabolite concentrations that are seen after systemic treatment with kappa opioid agonists appear not to involve VTA opioid receptors.
    BibTeX:
    @article{DEVINE1993,
      author = {DEVINE, DP and LEONE, P and POCOCK, D and WISE, RA},
      title = {DIFFERENTIAL INVOLVEMENT OF VENTRAL TEGMENTAL-MU, TEGMENTAL-DELTA AND KAPPA-OPIOID RECEPTORS IN MODULATION OF BASAL MESOLIMBIC DOPAMINE RELEASE - IN-VIVO MICRODIALYSIS STUDIES},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1993},
      volume = {266},
      number = {3},
      pages = {1236-1246}
    }
    
    Di Chiara, G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction {2002} BEHAVIOURAL BRAIN RESEARCH
    Vol. {137}({1-2}), pp. {75-114} 
    article  
    Abstract: Drug addiction can be conceptualized as a disturbance of behavior motivated by drug-conditioned incentives. This abnormality has been explained by Incentive-Sensitization and Allostatic-Counteradaptive theories as the result of non-associative mechanisms acting at the stage of the expression of incentive motivation and responding for drug reinforcement. Each one of these theories, however, does not account per se for two basic properties of the motivational disturbance of drug addiction: (1) focussing on drug-at the expenses of non-drug-incentives; (2) virtual irreversibility. To account for the above aspects we have proposed an associative learning hypothesis. According to this hypothesis the basic disturbance of drug addiction takes place at the stage of acquisition of motivation and in particular of Pavlovian incentive learning. Drugs share with non-drug rewards the property of stimulating dopamine (DA) transmission in the nucleus accumbens shell but this effect does not undergo habituation upon repeated drug exposure, as instead is the case of non-drug rewards. Repetitive, non-decremental stimulation of DA transmission by drugs in the nucleus accumbens septi (NAc) shell abnormally strenghtens stimulus-drug associations. Thus, stimuli contingent upon drug reward acquire powerful incentive properties after a relatively limited number of predictive associations with the drug and become particularly resistant to extinction. Non-contingent occurrence of drug-conditioned incentive cues or contexts strongly facilitates and eventually reinstates drug self-administration. Repeated drug exposure also induces a process of sensitization of drug-induced stimulation of DA transmission in the NAc core. The precise significance of this adaptive change for the mechanism of drug addiction is unclear given the complexity and uncertainties surrounding the role of NAc core DA in responding but might be more directly related to instrumental performance. (C) 2002 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{DiChiara2002,
      author = {Di Chiara, G},
      title = {Nucleus accumbens shell and core dopamine: differential role in behavior and addiction},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {2002},
      volume = {137},
      number = {1-2},
      pages = {75-114}
    }
    
    Di Chiara, G. Role of dopamine in the behavioural actions of nicotine related to addiction {2000} EUROPEAN JOURNAL OF PHARMACOLOGY
    Vol. {393}({1-3, Sp. Iss. SI}), pp. {295-314} 
    article  
    Abstract: Experimental impairment of dopamine function by 6-hydroxydopamine lesions or by dopamine receptor antagonists shows that dopamine is involved in nicotine's discriminative stimulus properties, nicotine-induced facilitation of intracranial self-stimulation, intravenous nicotine self-administration, nicotine conditioned place-preference and nicotine-induced disruption of latent inhibition. Therefore, nicotine depends on dopamine for those behavioural effects that are most relevant for its reinforcing properties and are likely to be the basis of the abuse liability of tobacco smoke. On the other hand, in vivo monitoring studies show that nicotine stimulates dopamine transmission in specific brain areas and in particular, in the shell of the nucleus accumbens and in areas of the extended amygdala. These effects of nicotine resemble those of a reward like food except that nicotine-induced release of dopamine does not undergo single-trial, long-lasting habituation. It is speculated that repeated non-habituating stimulation of dopamine release by nicotine in the nucleus accumbens shell abnormally facilitates associative stimulus-reward learning. Acute effects of nicotine on dopamine transmission undergo acute and chronic tolerance; with repeated, discontinuous exposure, sensitization of nicotine-induced stimulation of dopamine release in the nucleus accumbens core takes place while the response in the shell is reduced. It is speculated that these adaptive changes are the substrate of a switch from abnormal incentive responding controlled by consequences (action-outcome responding) into abnormal habit responding, triggered by conditional stimuli and automatically driven by action schemata relatively independent from nicotine reward. These two modalities might coexist, being utilized alternatively in relation to the availability of tobacco. Unavailability of tobacco disrupts the automatic, implicit modality of abnormal habit responding switching responding into the explicit, conscious modality of incentive drug-seeking and craving. (C) 2000 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{DiChiara2000,
      author = {Di Chiara, G},
      title = {Role of dopamine in the behavioural actions of nicotine related to addiction},
      journal = {EUROPEAN JOURNAL OF PHARMACOLOGY},
      year = {2000},
      volume = {393},
      number = {1-3, Sp. Iss. SI},
      pages = {295-314},
      note = {Congress on Neuronal Nicotinic Receptors - From Stucture to Therapeutics, VENICE, ITALY, OCT 01-04, 1999}
    }
    
    Di Chiara, G. Drug addiction as dopamine-dependent associative learning disorder {1999} EUROPEAN JOURNAL OF PHARMACOLOGY
    Vol. {375}({1-3, Sp. Iss. SI}), pp. {13-30} 
    article  
    Abstract: Natural rewards preferentially stimulate dopamine transmission in the nucleus accumbens shell. This effect undergoes adaptive changes (one-trial habituation, inhibition by appetitive stimuli) that are consistent with a role of nucleus accumbens shell dopamine in associative reward-related learning. Experimental studies with a variety of paradigms confirm this role. A role in associative stimulus-reward learning can provide an explanation for the extinction-like impairment of primary reinforcement that led Wise to propose the `anhedonia hypothesis'. Addictive drugs share with natural rewards the property of stimulating dopamine transmission preferentially in the nucleus accumbens shell. This response, however, in contrast to that to natural rewards, is not subjected to one-trial habituation. Resistance to habituation allows drugs to activate dopamine transmission in the shell non-decrementally upon repeated self-administration. It is hypothesized that this process abnormally strengthens stimulus-drug associations thus resulting in the attribution of excessive motivational value to discrete stimuli or contexts predictive of drug availability. Addiction is therefore the expression of the excessive control over behaviour acquired by drug-related stimuli as a result of abnormal associative learning following repeated stimulation of dopamine transmission in the nucleus accumbens shell. (C) 1999 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{DiChiara1999,
      author = {Di Chiara, G},
      title = {Drug addiction as dopamine-dependent associative learning disorder},
      journal = {EUROPEAN JOURNAL OF PHARMACOLOGY},
      year = {1999},
      volume = {375},
      number = {1-3, Sp. Iss. SI},
      pages = {13-30},
      note = {1st European Journal of Pharmacology Spring Meeting, ZEIST, NETHERLANDS, APR 16-18, 1999}
    }
    
    Di Chiara, G. A motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use {1998} JOURNAL OF PSYCHOPHARMACOLOGY
    Vol. {12}({1}), pp. {54-67} 
    article  
    Abstract: The effects of drugs and substances of abuse on central dopamine (DA) transmission studied by in, vivo monitoring techniques have been examined and compared with those of conventional reinforcers and in particular with food. The similarities and differences in the action of drugs and conventional reinforcers on DA transmission can provide the basis for an hypothesis of the mechanism of drug addiction and compulsive drug use. This hypothesis states that drug addiction is due to excessive control over behaviour exerted by drug-related stimuli as a result of abnormal motivational learning induced by repeated drug exposure. Such abnormal motivational learning would derive from the repetitive non-habituating property of drugs of abuse to activate DA transmission phasically in the nucleus accumbens (NAc) `shell'. Thus, activation of DA transmission by conventional reinforcers is under strong inhibitory control by previous exposure to the reinforcer (habituation); this, however, is not the case with drug reinforcers. Repetitive, non-adaptive release of DA in the NAc `shell' by drugs of abuse would result in abnormal strengthening of stimulus-reward (incentive learning) and stimulus-response associations (habit learning) that constitute the basis for craving and compulsive drug use.
    BibTeX:
    @article{DiChiara1998,
      author = {Di Chiara, G},
      title = {A motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use},
      journal = {JOURNAL OF PSYCHOPHARMACOLOGY},
      year = {1998},
      volume = {12},
      number = {1},
      pages = {54-67}
    }
    
    Di Chiara, G., Bassareo, V., Fenu, S., De Luca, M., Spina, L., Cadoni, C., Acquas, E., Carboni, E., Valentini, V. & Lecca, D. Dopamine and drug addiction: the nucleus accumbens shell connection {2004} NEUROPHARMACOLOGY
    Vol. {47}({Suppl. S}), pp. {227-241} 
    article DOI  
    Abstract: Microdialysis studies in animals have shown that addictive drugs preferentially increase extracellular dopamine (DA) in the n. accumbens (NAc). Brain imaging studies, while extending these finding to humans, have shown a correlation between psychostimulant-induced increase of extracellular DA in the striatum and self-reported measures of liking and `high' (euphoria). Although a correlate of drug reward independent from associative learning and performance is difficult to obtain in animals, conditioned taste avoidance (CTA) might meet these requirements. Addictive drugs induce CTA to saccharin most likely as a result of anticipatory contrast of saccharin over drug reward. Consistently with a role of DA in drug reward, D2 or combined D1/D2 receptor blockade abolishes cocaine, amphetamine and nicotine CTA. Intracranial self-administration studies with mixtures of D1 and D2 receptor agonists point to the NAc shell as the critical site of DA reward. NAc shell DA acting on D1 receptors is also involved in Pavlovian learning through pre-trial and post-trial consolidation mechanisms and in the utilization of spatial short-term memory for goal-directed behavior. Stimulation of NAc shell DA transmission by addictive drugs is shared by a natural reward like food but lacks its adaptive properties (habituation and inhibition by predictive stimuli). These peculiarities of drug-induced stimulation of DA transmission in the NAc shell result in striking differences in the impact of drug-conditioned stimuli on DA transmission. It is speculated that drug addiction results from the impact exerted on behavior by the abnormal DA stimulant properties acquired by drug-conditioned stimuli as a result of their association with addictive drugs. (C) 2004 Elsevier Ltd. All rights reserved.
    BibTeX:
    @article{DiChiara2004,
      author = {Di Chiara, G and Bassareo, V and Fenu, S and De Luca, MA and Spina, L and Cadoni, C and Acquas, E and Carboni, E and Valentini, V and Lecca, D},
      title = {Dopamine and drug addiction: the nucleus accumbens shell connection},
      journal = {NEUROPHARMACOLOGY},
      year = {2004},
      volume = {47},
      number = {Suppl. S},
      pages = {227-241},
      doi = {{10.1016/j.neuropharm.2004.06.032}}
    }
    
    DIAZ, J., LEVESQUE, D., LAMMERS, C., GRIFFON, N., MARTRES, M., SCHWARTZ, J. & SOKOLOFF, P. PHENOTYPICAL CHARACTERIZATION OF NEURONS EXPRESSING THE DOPAMINE D-3 RECEPTOR IN THE RAT-BRAIN {1995} NEUROSCIENCE
    Vol. {65}({3}), pp. {731-745} 
    article  
    Abstract: We have established the cellular distribution of the dopamine D-3 receptor using tritiated 7-hydroxy-N-N-di-n-propyl-2-aminotetralin and a complementary RNA probe to visualize autoradiographically the protein in binding studies and the gene transcripts by in situ hybridization, respectively. Studies with these two markers confirm the restricted expression of the D-3 receptor in few brain areas, i.e. mainly the ventral striatal complex, the substantia nigra-ventral tegmental area and the cerebellum. In nucleus accumbens, the D-3 receptor was mainly expressed in medium-sized neurons of the rostral pole and ventromedial shell subdivisions, but not of the core or septal pole, i.e. accumbal subdivisions expressing the D-2 receptor. In the ventromedial shell, about 60% of the D-3 receptor-expressing neurons were neurotensin neurons, presumably projecting to the ventral pallidum. In the islands of Calleja, both D-3 receptor binding and messenger RNA were abundant in the entire population of granule cells. These cells are known to make sparse contacts with dopaminergic axons and also to express the D-1 receptor. In the mesencephalon, low levels of D-3 messenger RNA were detected in few dopamine neurons of substantia nigra pars lateralis and ventral tegmental area. In addition, some D-3 receptor binding but not messenger RNA was detected in medial substantia nigra and lateral ventral tegmental area, where the receptor is presumably located presynaptically on afferents. In the archicerebellum, Purkinje cell perikarya in lobules 9 and 10 expressed the D-3 receptor messenger RNA, whereas binding sites were found in the molecular layer, where corresponding dendrites but no known dopaminergic projection from mesencephalon are found. The occurrence of D-3 receptor gene expression in some brain areas receiving low dopamine innervation supports the hypothesis that this receptor may mediate Iron-synaptic actions of dopamine.
    BibTeX:
    @article{DIAZ1995,
      author = {DIAZ, J and LEVESQUE, D and LAMMERS, CH and GRIFFON, N and MARTRES, MP and SCHWARTZ, JC and SOKOLOFF, P},
      title = {PHENOTYPICAL CHARACTERIZATION OF NEURONS EXPRESSING THE DOPAMINE D-3 RECEPTOR IN THE RAT-BRAIN},
      journal = {NEUROSCIENCE},
      year = {1995},
      volume = {65},
      number = {3},
      pages = {731-745}
    }
    
    DICHIARA, G. THE ROLE OF DOPAMINE IN DRUG-ABUSE VIEWED FROM THE PERSPECTIVE OF ITS ROLE IN MOTIVATION {1995} DRUG AND ALCOHOL DEPENDENCE
    Vol. {38}({2}), pp. {95-137} 
    article  
    Abstract: Drugs of abuse share with conventional reinforcers the activation of specific neural pathways in the CNS that are the substrate of their motivational properties. Dopamine is recognized as the transmitter of one such neural pathway, being involved in at least three major aspects of motivation: modulation of motivational state, acquisition (incentive learning) and expression of incentive properties by motivational stimuli. Drugs of abuse of different pharmacological classes stimulate in the low dose range dopamine transmission particularly in the ventral striatum. Apart from psychostimulants, the evidence that stimulation of dopamine transmission by drugs of abuse provides the primary motivational stimulus for drug self-administration is either unconvincing or negative. However, stimulation of dopamine transmission is essential for the activational properties of drugs of abuse and might be instrumental for the acquisition of responding to drug-related incentive stimuli (incentive learning). Dopamine is involved in the induction and in the expression of behavioural sensitization by repeated exposure to various drugs of abuse. Sensitization to the dopamine-stimulant properties of specific drug classes leading to facilitation of incentive learning of drug-related stimuli might account for the strong control over behaviour exerted by these stimuli in the addiction state. Withdrawal from drugs of abuse results in a reduction in basal dopamine transmission in vivo and in reduced responding for conventional reinforcers. Although these changes are likely to be the expression of a state of dependence of the dopamine system their contribution to the motivational state of drug addiction is unclear.
    BibTeX:
    @article{DICHIARA1995,
      author = {DICHIARA, G},
      title = {THE ROLE OF DOPAMINE IN DRUG-ABUSE VIEWED FROM THE PERSPECTIVE OF ITS ROLE IN MOTIVATION},
      journal = {DRUG AND ALCOHOL DEPENDENCE},
      year = {1995},
      volume = {38},
      number = {2},
      pages = {95-137}
    }
    
    DICHIARA, G. & IMPERATO, A. OPPOSITE EFFECTS OF MU-OPIATE AND KAPPA-OPIATE AGONISTS ON DOPAMINE RELEASE IN THE NUCLEUS ACCUMBENS AND IN THE DORSAL CAUDATE OF FREELY MOVING RATS {1988} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {244}({3}), pp. {1067-1080} 
    article  
    BibTeX:
    @article{DICHIARA1988,
      author = {DICHIARA, G and IMPERATO, A},
      title = {OPPOSITE EFFECTS OF MU-OPIATE AND KAPPA-OPIATE AGONISTS ON DOPAMINE RELEASE IN THE NUCLEUS ACCUMBENS AND IN THE DORSAL CAUDATE OF FREELY MOVING RATS},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1988},
      volume = {244},
      number = {3},
      pages = {1067-1080}
    }
    
    DICHIARA, G. & NORTH, R. NEUROBIOLOGY OF OPIATE ABUSE {1992} TRENDS IN PHARMACOLOGICAL SCIENCES
    Vol. {13}({5}), pp. {185-193} 
    article  
    Abstract: Opiates interact with cell surface receptors on neurons involved in the transmission of information along neural pathways that are related to behaviours essential for the life of the self and of the species. Opiates are provided with powerful and multifaceted rewarding properties that are fundamental for the acquisition, maintenance and relapse of opiate addiction. Gaetano Di Chiara and Alan North argue that both dopaminergic and non-dopaminergic systems are involved in opiate reward, and that opiate addiction results from adaptive and learning processes involving both positive reinforcing mechanisms related to the rewarding properties of opiates and negative reinforcing mechanisms related to the aversive properties of withdrawal in dependent subjects.
    BibTeX:
    @article{DICHIARA1992,
      author = {DICHIARA, G and NORTH, RA},
      title = {NEUROBIOLOGY OF OPIATE ABUSE},
      journal = {TRENDS IN PHARMACOLOGICAL SCIENCES},
      year = {1992},
      volume = {13},
      number = {5},
      pages = {185-193}
    }
    
    Dixon, A., Gubitz, A., Sirinathsinghji, D., Richardson, P. & Freeman, T. Tissue distribution of adenosine receptor mRNAs in the rat {1996} BRITISH JOURNAL OF PHARMACOLOGY
    Vol. {118}({6}), pp. {1461-1468} 
    article  
    Abstract: 1 A degree of ambiguity and uncertainty exists concerning the distribution of mRNAs encoding the four cloned adenosine receptors. In order to consolidate and extend current understanding in this area, the expression of the adenosine receptors has been examined in the rat by use of in situ hybridisation and the reverse transcription-polymerase chain reaction (RT-PCR). 2 In accordance with earlier studies, in situ hybridisation revealed that the adenosine A(1) receptor was widely expressed in the brain, whereas A(2A) receptor mRNA was restricted to the striatum, nucleus accumbens and olfactory tubercle. In addition, A(1) receptor mRNA was detected in large striatal cholinergic interneurones, 26% of these neurones were also found to express the A(2A) receptor gene. Central levels of mRNAs encoding adenosine A(2B) and A(3) receptors were, however, below the detection limits of in situ hybridisation. 3 The more sensitive technique of RT-PCR was then employed to investigate the distribution of adenosine receptor mRNAs in the central nervous system (CNS) and a wide range of peripheral tissues. As a result, many novel sites of adenosine receptor gene expression were identified. A(1) receptor expression has now been found in the heart, aorta, liver, kidney, eye and bladder. These observations are largely consistent with previous functional data. A(2A) receptor mRNA was detected in all brain regions tested, demonstrating that expression of this receptor is not restricted to the basal ganglia. In the periphery A(2A) receptor mRNA was also found to be more widely distributed than generally recognised. The ubiquitous distribution of the A(2B) receptor is shown for the first time, A(2B) mRNA was detected at various levels in all rat tissues studied. Expression of the gene encoding the adenosine A(3) receptor was also found to be widespread in the rat, message detected throughout the CNS and in many peripheral tissues. This pattern of expression is similar to that observed in man and sheep, which had previously been perceived to possess distinct patterns of A(3) receptor gene expression in comparison to the rat. 4 In summary, this work has comprehensively studied the expression of all the cloned adenosine receptors in the rat, and in so doing, resolves some of the uncertainty over where these receptors might act to control physiological processes mediated by adenosine.
    BibTeX:
    @article{Dixon1996,
      author = {Dixon, AK and Gubitz, AK and Sirinathsinghji, DJS and Richardson, PJ and Freeman, TC},
      title = {Tissue distribution of adenosine receptor mRNAs in the rat},
      journal = {BRITISH JOURNAL OF PHARMACOLOGY},
      year = {1996},
      volume = {118},
      number = {6},
      pages = {1461-1468}
    }
    
    DRAGO, J., GERFEN, C., LACHOWICZ, J., STEINER, H., HOLLON, T., LOVE, P., OOI, G., GRINBERG, A., LEE, E., HUANG, S., BARTLETT, P., JOSE, P., SIBLEY, D. & WESTPHAL, H. ALTERED STRIATAL FUNCTION IN A MUTANT MOUSE LACKING D-1A DOPAMINE-RECEPTORS {1994} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {91}({26}), pp. {12564-12568} 
    article  
    Abstract: Of the five known dopamine receptors, D-1A and D-2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D-1A receptors expressed by direct output neurons and D-2 receptors expressed by indirect output neurons. To further examine the interaction of D-1A and D-2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D-1A receptors (D-1A-/-) D-1a-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D-1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D-1A receptor binding was absent in striatal sections from D-1A-/- mice. Striatal neurons normally expressing functional D-1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D-1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D-2 receptors, are unaffected. These findings show that D-1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway.
    BibTeX:
    @article{DRAGO1994,
      author = {DRAGO, J and GERFEN, CR and LACHOWICZ, JE and STEINER, H and HOLLON, TR and LOVE, PE and OOI, GT and GRINBERG, A and LEE, EJ and HUANG, SP and BARTLETT, PF and JOSE, PA and SIBLEY, DR and WESTPHAL, H},
      title = {ALTERED STRIATAL FUNCTION IN A MUTANT MOUSE LACKING D-1A DOPAMINE-RECEPTORS},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1994},
      volume = {91},
      number = {26},
      pages = {12564-12568}
    }
    
    Drevets, W. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders {2001} CURRENT OPINION IN NEUROBIOLOGY
    Vol. {11}({2}), pp. {240-249} 
    article  
    Abstract: Neuroimaging technology has provided unprecedented opportunities for elucidating the anatomical correlates of major depression. The knowledge gained from imaging research and from the postmortem studies that have been guided by imaging data is catalyzing a paradigm shift in which primary mood disorders are conceptualized as illnesses that involve abnormalities of brain structure, as well as of brain function. These data suggest specific hypotheses regarding the neural mechanisms underlying pathological emotional processing in mood disorders. They particularly support a role for dysfunction within the prefrontal cortical and striatal systems that normally modulate limbic and brainstem structures involved in mediating emotional behavior in the pathogenesis of depressive symptoms.
    BibTeX:
    @article{Drevets2001,
      author = {Drevets, WC},
      title = {Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders},
      journal = {CURRENT OPINION IN NEUROBIOLOGY},
      year = {2001},
      volume = {11},
      number = {2},
      pages = {240-249}
    }
    
    Drevets, W., Gautier, C., Price, J., Kupfer, D., Kinahan, P., Grace, A., Price, J. & Mathis, C. Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria {2001} BIOLOGICAL PSYCHIATRY
    Vol. {49}({2}), pp. {81-96} 
    article  
    Abstract: Background: Studies in experimental animals have implicated the mesolimbic dopaminergic projections into the ventral striatum in the neural processes underlying behavioral reinforcement and motivated behavior; however, understanding the relationship between subjective emotional experience and ventral striatal dopamine (DA) release has awaited human studies. Using positron emission tomography (PET), we correlated the change in endogenous dopamine concentrations following dextroamphetamine (AMPH) administration with the associated hedonic response in human subjects and compared the strength of this correlation across striatal subregions, Methods: We obtained PET measures of [C-11]raclopride specific binding to DA D2/D3 receptors before and after AMPH injection (0.3 mg/kg IV) in seven healthy subjects. The change in [C-11]raclopride binding potential (Delta BP) induced by AMPH pretreatment and the correlation between Delta BP and the euphoric response to AMPH were compared between the anteroventral striatum (AVS; comprised of accumbens area, ventromedial caudate, and anteroventral putamen) and the dorsal caudate (DCA) using an MRI-based region of interest analysis of the PET data. Results: The mean Delta BP was greater in the AVS than in the DCA (p < .05). The AMPH-induced changes in euphoria analog scale scores correlated inversely with BP in the AVS (r = -.95; p < .001), but not in the DCA (r = .30, ns). Post hoc assessments showed that changes in tension-anxiety ratings correlated positively with BP in the AVS (r = .80; p [uncorrected] < .05) and that similar relationships may exist between BP and emotion ratings in the ventral putamen (as were found in the AVS), Conclusions: The preferential sensitivity of the ventral striatum to the DA releasing effects of AMPH previously demonstrated in experimental animals extends to humans. The magnitude of ventral striatal DA release correlates positively with the hedonic response to AMPH. (C) 2001 Society of Biological Psychiatry.
    BibTeX:
    @article{Drevets2001a,
      author = {Drevets, WC and Gautier, C and Price, JC and Kupfer, DJ and Kinahan, PE and Grace, AA and Price, JL and Mathis, CA},
      title = {Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria},
      journal = {BIOLOGICAL PSYCHIATRY},
      year = {2001},
      volume = {49},
      number = {2},
      pages = {81-96}
    }
    
    Du, Y., Ma, Z., Lin, S., Dodel, R., Gao, F., Bales, K., Triarhou, L., Chernet, E., Perry, K., Nelson, D., Luecke, S., Phebus, L., Bymaster, F. & Paul, S. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease {2001} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {98}({25}), pp. {14669-14674} 
    article  
    Abstract: Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MPP+)-mediated iNOS expression and NO-induced neurotoxicity, but MPP+-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MPP+-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.
    BibTeX:
    @article{Du2001,
      author = {Du, YS and Ma, ZZ and Lin, SZ and Dodel, RC and Gao, F and Bales, KR and Triarhou, LC and Chernet, E and Perry, KW and Nelson, DLG and Luecke, S and Phebus, LA and Bymaster, FP and Paul, SM},
      title = {Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {2001},
      volume = {98},
      number = {25},
      pages = {14669-14674}
    }
    
    Duncan, G., Knapp, D. & Breese, G. Neuroanatomical characterization of Fos induction in rat behavioral models of anxiety {1996} BRAIN RESEARCH
    Vol. {713}({1-2}), pp. {79-91} 
    article  
    Abstract: Immunohistochemical staining for Fos-like immunoreactivity (Fos-LI) was used to map functional activation in discrete brain regions of rats processed in three empirical models of anxiety: foot shock avoidance responding in a shuttle box, the elevated plus maze, and an air puff-induced ultrasonic vocalization test. The avoidance test and elevated plus maze induced prominent Fos-LI in select brain regions, including the medial prefrontal, cingulate, and ventrolateral orbital cortices, taenia tecta, nucleus accumbens, paraventricular nucleus of the hypothalamus, medial nucleus of the amygdala and lateral septum. Air puff stimuli that produced ultrasonic vocalizations induced Fos-LI to a more limited extent compared to the plus maze and avoidance test, with only the medial prefrontal cortex, medial nucleus of the amygdala, and lateral septum being significantly affected by air-puff. Even though the sensory stimuli and environmental conditions associated with the three anxiety models were markedly different, specific common forebrain regions were affected, i.e. the medial prefrontal cortex, medial amygdala, and lateral septum. It is hypothesized that these regions are components of a circuit in the rat brain related to anxiety or distress. To determine the potential relationship between generalized arousal and the observed induction of Fos-LI in the anxiety models, rats were tested in a non-aversive situation involving marked behavioral activation. Accordingly, after vigorous bar pressing behavior for reinforcement with sweetened condensed milk, induction of Fos-LI was minimal and comparable to that in unhandled control rats. These latter data indicate that the distinctive neuroanatomical patterns of Fos-LI observed in the paradigms related to anxiety were not simply due to generalized behavioral activation. In summary, select common brain regions were identified that express Fos-LI in empirical models of anxiety. These data provide a functional framework to explore neuroanatomical sites of action of psychotherapeutic drugs that influence behavioral responses in these tasks.
    BibTeX:
    @article{Duncan1996,
      author = {Duncan, GE and Knapp, DJ and Breese, GR},
      title = {Neuroanatomical characterization of Fos induction in rat behavioral models of anxiety},
      journal = {BRAIN RESEARCH},
      year = {1996},
      volume = {713},
      number = {1-2},
      pages = {79-91}
    }
    
    Einat, H., Yuan, P., Gould, T., Li, J., Du, J., Zhang, L., Manji, H. & Chen, G. The role of the extracellular signal-regulated kinase signaling pathway in mood modulation {2003} JOURNAL OF NEUROSCIENCE
    Vol. {23}({19}), pp. {7311-7316} 
    article  
    Abstract: The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.
    BibTeX:
    @article{Einat2003,
      author = {Einat, H and Yuan, PX and Gould, TD and Li, JL and Du, JH and Zhang, L and Manji, HK and Chen, G},
      title = {The role of the extracellular signal-regulated kinase signaling pathway in mood modulation},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2003},
      volume = {23},
      number = {19},
      pages = {7311-7316}
    }
    
    Elliott, R., Friston, K. & Dolan, R. Dissociable neural responses in human reward systems {2000} JOURNAL OF NEUROSCIENCE
    Vol. {20}({16}), pp. {6159-6165} 
    article  
    Abstract: Reward is one of the most important influences shaping behavior. Single-unit recording and lesion studies in experimental animals have implicated a number of regions in response to reinforcing stimuli, in particular regions of the extended limbic system and the ventral striatum. In this experiment, functional neuroimaging was used to assess neural response within human reward systems under different psychological contexts. Nine healthy volunteers were scanned using functional magnetic resonance imaging during the performance of a gambling task with financial rewards and penalties. We demonstrated neural sensitivity of midbrain and ventral striatal regions to financial rewards and hippocampal sensitivity to financial penalties. Furthermore, we show that neural responses in globus pallidus, thalamus, and subgenual cingulate were specific to high reward levels occurring in the context of increasing reward. Responses to both reward level in the context of increasing reward and penalty level in the context of increasing penalty were seen in caudate, insula, and ventral prefrontal cortex. These results demonstrate dissociable neural responses to rewards and penalties that are dependent on the psychological context in which they are experienced.
    BibTeX:
    @article{Elliott2000,
      author = {Elliott, R and Friston, KJ and Dolan, RJ},
      title = {Dissociable neural responses in human reward systems},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2000},
      volume = {20},
      number = {16},
      pages = {6159-6165}
    }
    
    Elliott, R., Newman, J., Longe, O. & Deakin, J. Differential response patterns in the striatum and orbitofrontal cortex to financial reward in humans: A parametric functional magnetic resonance imaging study {2003} JOURNAL OF NEUROSCIENCE
    Vol. {23}({1}), pp. {303-307} 
    article  
    Abstract: Responses to monetary reward in humans have been assessed in a number of recent functional imaging studies, and it is clear that the neuronal substrates of financial reinforcement overlap extensively with regions responding to primary reinforcers, such as food. Money has the practical advantage of being an objectively quantifiable reinforcer. In this study, we exploit this advantage using a parametric functional magnetic resonance imaging design to look at the patterns of responding to systematically varying reward values. Twelve healthy volunteers were scanned during performance of a rewarded target detection task, in which the reward value varied between task blocks. We observed three distinct patterns of responding in different regions. Amygdala, striatum, and dopaminergic midbrain responded to the presence of rewards, regardless of value. In contrast, premotor cortex showed a linear increase in response with increasing reward value. Finally, medial and lateral foci of orbitofrontal cortex responded nonlinearly, such that response was enhanced for the lowest and highest reward values relative to the midrange. These results suggest functional distinction in response patterns within a distributed reward system.
    BibTeX:
    @article{Elliott2003,
      author = {Elliott, R and Newman, JL and Longe, OA and Deakin, JFW},
      title = {Differential response patterns in the striatum and orbitofrontal cortex to financial reward in humans: A parametric functional magnetic resonance imaging study},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2003},
      volume = {23},
      number = {1},
      pages = {303-307}
    }
    
    Epping-Jordan, M., Watkins, S., Koob, G. & Markou, A. Dramatic decreases in brain reward function during nicotine withdrawal {1998} NATURE
    Vol. {393}({6680}), pp. {76-79} 
    article  
    Abstract: Tobacco smoking is a worldwide public health problem. In the United States alone, over 400,000 deaths and 50 billion in medical costs annually are directly attributed to smoking(1). Accumulated evidence indicates that nicotine is the component of tobacco smoke that leads to addiction(2), but the means by which nicotine produces addiction remain unclear. Nicotine is less effective as a positive reinforcer than other drugs of abuse in non-dependent animals(3). Nevertheless, nicotine-withdrawal symptoms, including depressed mood, anxiety, irritability and craving(4,5) in dependent subjects may contribute to the addictive liability of nicotine(6,7). We show here that spontaneous nicotine withdrawal in rats resulted in a significant decrease in brain reward function, as measured by elevations in brain reward thresholds, which persisted for four days. Further, systemic injections of a competitive nicotinic-receptor antagonists led to a dose-dependent increase in brain reward thresholds in chronic nicotine-treated rats. The decreased function in brain reward systems during nicotine withdrawal is comparable in magnitude and duration to that of other major drugs of abuse(9-13), and may constitute an important motivational factor that contributes to craving, relapse and continued tobacco consumption in humans(7).
    BibTeX:
    @article{Epping-Jordan1998,
      author = {Epping-Jordan, MP and Watkins, SS and Koob, GF and Markou, A},
      title = {Dramatic decreases in brain reward function during nicotine withdrawal},
      journal = {NATURE},
      year = {1998},
      volume = {393},
      number = {6680},
      pages = {76-79}
    }
    
    Everitt, B., Dickinson, A. & Robbins, T. The neuropsychological basis of addictive behaviour {2001} BRAIN RESEARCH REVIEWS
    Vol. {36}({2-3, Sp. Iss. SI}), pp. {129-138} 
    article  
    Abstract: The argument advanced in this review is that drug addiction can be understood in terms of normal learning and memory systems of the brain which, through the actions of chronically self-administered drugs, are pathologically subverted, thereby leading to the establishment of compulsive drug-seeking habits, strengthened by the motivational impact of drug-associated stimuli and occurring at the expense of other sources of reinforcement. We review data from our studies that have utilized procedures which reveal the various influences of pavlovian stimuli on goal-directed behaviour, namely discriminated approach, pavlovian-to-instrumental transfer and conditioned reinforcement, in order to demonstrate their overlapping and also unique neural bases. These fundamental studies are also reviewed in the context of the neural and psychological mechanisms underlying drug-seeking behaviour that is under the control of drug-associated environmental stimuli. The ways in which such drug-seeking behaviour becomes compulsive and habitual, as well as the propensity for relapse to drug-seeking even after long periods of relapse, are discussed in terms of the aberrant learning set in train by the effects of self-administered drugs on plastic processes in limbic cortical-ventral striatal systems. (C) 2001 Elsevier Science BY All rights reserved.
    BibTeX:
    @article{Everitt2001,
      author = {Everitt, BJ and Dickinson, A and Robbins, TW},
      title = {The neuropsychological basis of addictive behaviour},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {2001},
      volume = {36},
      number = {2-3, Sp. Iss. SI},
      pages = {129-138},
      note = {Symposium of the Swiss-National-Science-Foundation, WARTH, SWITZERLAND, MAR 29-31, 2001}
    }
    
    EVERITT, B., MORRIS, K., OBRIEN, A. & ROBBINS, T. THE BASOLATERAL AMYGDALA VENTRAL STRIATAL SYSTEM AND CONDITIONED PLACE PREFERENCE - FURTHER EVIDENCE OF LIMBIC STRIATAL INTERACTIONS UNDERLYING REWARD-RELATED PROCESSES {1991} NEUROSCIENCE
    Vol. {42}({1}), pp. {1-18} 
    article  
    Abstract: The effects on the expression of a conditioned place preference of bilateral, excitotoxic amino acid-induced lesions of the basolateral region of the amygdala, or the ventral striatum, or asymmetric, unilateral lesions of both structures were studied. The place preference was conditioned by exposing hungry rats to sucrose in a distinctive environment. Following acquisition, bilateral quisqualate-induced lesions of the basolateral amygdala, as well as bilateral quinolinate-induced lesions of the ventral striatum, abolished the conditioned place preference. Bilateral ventromedial, but not dorsolateral, quinolinate-induced caudate-putamen lesions attenuated the place preference. Combining a unilateral lesion of the basolateral amygdala with a contralateral lesion of the ventral striatum also disrupted the conditioned place preference. These data provide further support for the hypothesis that the basolateral amygdala and ventral striatum are important parts of a neural system subserving stimulus-reward associations.
    BibTeX:
    @article{EVERITT1991,
      author = {EVERITT, BJ and MORRIS, KA and OBRIEN, A and ROBBINS, TW},
      title = {THE BASOLATERAL AMYGDALA VENTRAL STRIATAL SYSTEM AND CONDITIONED PLACE PREFERENCE - FURTHER EVIDENCE OF LIMBIC STRIATAL INTERACTIONS UNDERLYING REWARD-RELATED PROCESSES},
      journal = {NEUROSCIENCE},
      year = {1991},
      volume = {42},
      number = {1},
      pages = {1-18}
    }
    
    Everitt, B., Parkinson, J., Olmstead, M., Arroyo, M., Robledo, P. & Robbins, T. Associative processes in addiction and reward - The role of amygdala-ventral striatal subsystems {1999}
    Vol. {877}ADVANCING FROM THE VENTRAL STRIATUM TO THE EXTENDED AMYGDALA - IMPLICATIONS FOR NEUROPSYCHIATRY AND DRUG ABUSE: IN HONOR OF LENNART HEIMER , pp. {412-438} 
    inproceedings  
    Abstract: Only recently have the functional implications of the organization of the ventral striatum, amygdala, and related limbic-cortical structures, and their neuroanatomical interactions begun to be clarified. Processes of activation and reward have long been associated with the NAcc and its dopamine innervation, but the precise relationships between these constructs have remained elusive. We have sought to enrich our understanding of the special role of the ventral striatum in coordinating the contribution of different functional subsystems to confer flexibility, as well as coherence and vigor, to goal-directed behavior, through different forms of associative learning. Such appetitive behavior comprises many subcomponents, some of which we have isolated in these experiments to reveal that, not surprisingly, the mechanisms by which an animal sequences responding to reach a goal are complex. The data reveal how the different components, pavlovian approach (or sign-tracking), conditioned reinforcement (whereby pavlovian stimuli control goal-directed action), and also more general response-invigorating processes (often called ``activation,'' ``stress,'' or ``drive'') may be integrated within the ventral striatum through convergent interactions of the amygdala, other limbic cortical structures, and the mesolimbic dopamine system to produce coherent behavior. The position is probably not far different when considering aversively motivated behavior. Although it may be necessary to employ simplified, even abstract, paradigms for isolating these mechanisms, their concerted action can readily be appreciated in an adaptive, functional setting, such as the responding by rats for intravenous cocaine under a second-order schedule of reinforcement. Here, the interactions of primary reinforcement, psychomotor activation, pavlovian conditioning, and the control that drug cues exert over the integrated drug-seeking response can be seen to operate both serially and concurrently. The power of our analytic techniques for understanding complex motivated behavior has been evident for some time. However, the crucial point is that we are now able to map these components with increasing certainty onto discrete amygdaloid, and other Limbic cortical-ventral striatal subsystems. The neural dissection of these mechanisms also serves an important theoretical purpose in helping to validate the various hypothetical constructs and further developing theory. Major challenges remain, not the least of which is an understanding of the operation of the ventral striatum together with its dopaminergic innervation and its interactions with the basolateral amygdala, hippocampal formation, and prefrontal cortex at a more mechanistic, neuronal level.
    BibTeX:
    @inproceedings{Everitt1999,
      author = {Everitt, BJ and Parkinson, JA and Olmstead, MC and Arroyo, M and Robledo, P and Robbins, TW},
      title = {Associative processes in addiction and reward - The role of amygdala-ventral striatal subsystems},
      booktitle = {ADVANCING FROM THE VENTRAL STRIATUM TO THE EXTENDED AMYGDALA - IMPLICATIONS FOR NEUROPSYCHIATRY AND DRUG ABUSE: IN HONOR OF LENNART HEIMER },
      year = {1999},
      volume = {877},
      pages = {412-438},
      note = {Conference on Advancing from the Ventral Striatum to the Extended Amygdala - Implications for Neuropsychiatry and Drug Abuse-In Honor of Lennart Heimer, CHARLOTTESVILLE, VIRGINIA, OCT 18-21, 1998}
    }
    
    Everitt, B. & Robbins, T. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion {2005} NATURE NEUROSCIENCE
    Vol. {8}({11}), pp. {1481-1489} 
    article DOI  
    Abstract: Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use-when a drug is voluntarily taken because it has reinforcing, often hedonic, effects-through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.
    BibTeX:
    @article{Everitt2005,
      author = {Everitt, BJ and Robbins, TW},
      title = {Neural systems of reinforcement for drug addiction: from actions to habits to compulsion},
      journal = {NATURE NEUROSCIENCE},
      year = {2005},
      volume = {8},
      number = {11},
      pages = {1481-1489},
      doi = {{10.1038/nn1579}}
    }
    
    Everitt, B. & Wolf, M. Psychomotor stimulant addiction: A neural systems perspective {2002} JOURNAL OF NEUROSCIENCE
    Vol. {22}({9}), pp. {3312-3320} 
    article  
    BibTeX:
    @article{Everitt2002,
      author = {Everitt, BJ and Wolf, ME},
      title = {Psychomotor stimulant addiction: A neural systems perspective},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2002},
      volume = {22},
      number = {9},
      pages = {3312-3320}
    }
    
    Fadda, F. & Rossetti, Z. Chronic ethanol consumption: From neuroadaptation to neurodegeneration {1998} PROGRESS IN NEUROBIOLOGY
    Vol. {56}({4}), pp. {385-431} 
    article  
    Abstract: In this review first we evaluate evidence on the role of the neurobiological alterations induced by chronic ethanol consumption in the development of ethanol tolerance, dependence and withdrawal. Secondly, we describe the neuropathological consequences of chronic ethanol on cognitive functions and on brain structures. Chronic alcohol consumption can induce alterations in the function and morphology of most if not all brain systems and structures. While tolerance mechanisms are unlikely to contribute to the neuroadaptive changes associated with ethanol dependence, it is otherwise clear that repeated high, intoxicating doses of ethanol trigger those neuroadaptive processes that lead to dependence and contribute to the manifestation of the abstinence syndrome upon withdrawal. An unbalance between inhibitory and excitatory neurotransmission is the most prominent neuroadaptive process induced by chronic ethanol consumption. Due to the diffuse glutamatergic innervation to all brain structures, the neuroadaptive alterations in excitatory neurotransmission can affect the function of most if not all of neurotransmitter systems. The expression of the withdrawal syndrome is the major causal factor for the onset and development of the neuropathological alterations. This suggests a link between the neuroadaptive mechanisms underlying the development of ethanol dependence and those underlying the functional and structural alterations induced by chronic ethanol. In animals and humans, specific alterations occur in the function and morphology of the diencephalon, medial temporal lobe structures, basal forebrain, frontal cortex and cerebellum, while other subcortical structures, such as the caudate nucleus, seem to be relatively spared. The neuropathological alterations in the function of mesencephalic and cortical structures are correlated with impairments in cognitive processes. In the brain of alcoholics, the prefrontal cortex and its subterritories seem particularly vulnerable to chronic ethanol, whether Korsakoff's syndrome is present or not. Due to the role of these cortical structures in cognitive functions and in the control of motivated behavior, functional alterations in this brain area may play an important role in the onset and development of alcoholism. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.
    BibTeX:
    @article{Fadda1998,
      author = {Fadda, F and Rossetti, ZL},
      title = {Chronic ethanol consumption: From neuroadaptation to neurodegeneration},
      journal = {PROGRESS IN NEUROBIOLOGY},
      year = {1998},
      volume = {56},
      number = {4},
      pages = {385-431}
    }
    
    Fanselow, M. Contextual fear, gestalt memories, and the hippocampus {2000} BEHAVIOURAL BRAIN RESEARCH
    Vol. {110}({1-2, Sp. Iss. SI}), pp. {73-81} 
    article  
    Abstract: This review examines the relationship between exploration and contextual fear conditioning. The fear acquired to places or contexts associated with aversive events is a form of Pavlovian conditioning. However, an initial period of exploration is necessary to allow the animal to form an integrated memory of the features of the context before conditioning can take place. The hippocampal formation plays a critical role in this process. Cells within the dorsal hippocampus are involved in the formation, storage and consolidation of this integrated representation of context. Projections from the subiculum to the nucleus accumbens regulate the exploration necessary for the acquisition of information about the features of the context. This model explains why electrolytic but not excitotoxic lesions of the dorsal hippocampus cause enhanced exploratory activity but both cause deficits in contextual fear. It also explains why retrograde amnesia of contextual fear is greater than anterograde amnesia. (C) 2000 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{Fanselow2000,
      author = {Fanselow, MS},
      title = {Contextual fear, gestalt memories, and the hippocampus},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {2000},
      volume = {110},
      number = {1-2, Sp. Iss. SI},
      pages = {73-81},
      note = {Annual Meeting of the Pavlovian-Society, DUSSELDORF, GERMANY, OCT 30-NOV 01, 1998}
    }
    
    Fienberg, A., Hiroi, N., Mermelstein, P., Song, W., Snyder, G., Nishi, A., Cheramy, A., O'Callaghan, J., Miller, D., Cole, D., Corbett, R., Haile, C., Cooper, D., Onn, S., Grace, A., Ouimet, C., White, F., Hyman, S., Surmeier, D., Girault, J., Nestler, E. & Greengard, P. DARPP-32: Regulator of the efficacy of dopaminergic neurotransmission {1998} SCIENCE
    Vol. {281}({5378}), pp. {838+} 
    article  
    Abstract: Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission.
    BibTeX:
    @article{Fienberg1998,
      author = {Fienberg, AA and Hiroi, N and Mermelstein, PG and Song, WJ and Snyder, GL and Nishi, A and Cheramy, A and O'Callaghan, JP and Miller, DB and Cole, DG and Corbett, R and Haile, CN and Cooper, DC and Onn, SP and Grace, AA and Ouimet, CC and White, FJ and Hyman, SE and Surmeier, DJ and Girault, JA and Nestler, EJ and Greengard, P},
      title = {DARPP-32: Regulator of the efficacy of dopaminergic neurotransmission},
      journal = {SCIENCE},
      year = {1998},
      volume = {281},
      number = {5378},
      pages = {838+}
    }
    
    Fink, G., Sumner, B., Rosie, R., Grace, O. & Quinn, J. Estrogen control of central neurotransmission: Effect on mood, mental state, and memory {1996} CELLULAR AND MOLECULAR NEUROBIOLOGY
    Vol. {16}({3}), pp. {325-344} 
    article  
    Abstract: 1. Estrogen exerts profound effects on mood, mental state and memory by acting on both `'classical'' monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action. 2. With respect to the effect of estrogen on central monoamine neurotransmission, low levels of estrogen in women are associated with the premenstrual syndrome, postnatal depression and post-menopausal depression. Sex differences in schizophrenia have also been attributed to estrogen. Previous studies have shown that estrogen stimulates a significant increase in dopamine, (D-2) receptors in the striatum. Here we show for the first time that estrogen also stimulates a significant increase in the density of 5-hydroxytryptamine(2A) (5-HT2A) binding sites in anterior frontal, cingulate and primary olfactory cortex and in the nucleus accumbens, areas of the brain concerned with the control of mood, mental state, cognition, emotion and behavior. These findings explain, for example, the efficacy of estrogen therapy or 5-HT uptake blockers such as fluoxetine in treating the depressive symptoms of the premenstrual syndrome, and suggest that the sex differences in schizophrenia may also be due to an action of estrogen mediated bq way of 5-HT2A receptors. 3. With respect to the effect of estrogen on central neuropeptide transmission, estrogen stimulates the expression of the arginine vasopressin (AVP) gene in the bed nucleus of the stria terminalis (BNST) in rodents. This results in a 100-fold increase in AVP mRNA in the BNST and a massive increase in AVP peptide in the BNST and its projections to the lateral septum and lateral habenula. The BNST-AVP system enhances and/or maintains `'social'' or `'olfactory'' memory, and thus provides a powerful model for correlating transcriptional control of neuropeptide gene expression with behavior. Whether similar mechanisms operate in the human remain to be determined. 4. These two examples of the action of estrogen on central neurotransmission are discussed in terms of their immediate clinical importance for the treatment of depressive symptoms, their use as powerful models for investigations on the steroid control of central neurotransmitter mechanisms, and the role of estrogen as `'Nature's'' psychoprotectant.
    BibTeX:
    @article{Fink1996,
      author = {Fink, G and Sumner, BEH and Rosie, R and Grace, O and Quinn, JP},
      title = {Estrogen control of central neurotransmission: Effect on mood, mental state, and memory},
      journal = {CELLULAR AND MOLECULAR NEUROBIOLOGY},
      year = {1996},
      volume = {16},
      number = {3},
      pages = {325-344}
    }
    
    Fitzgerald, L., Ortiz, J., Hamedani, A. & Nestler, E. Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: Common adaptations among cross-sensitizing agents {1996} JOURNAL OF NEUROSCIENCE
    Vol. {16}({1}), pp. {274-282} 
    article  
    Abstract: Behavioral and electrophysiological evidence suggests that glutamatergic neurotransmission plays an important role in some of the long-term effects of cocaine and other drugs of abuse on brain function. We therefore examined the effect of repeated cocaine treatment on glutamate receptor subunit expression in central dopamine (DA) pathways implicated in many of cocaine's behavioral actions. By immunoblotting procedures using subunit-specific antibodies, we found that repeated, but not acute, cocaine treatment increased the levels of immunoreactivity of GluR1 (an AMPA receptor subunit) and NMDAR1 (an NMDA receptor subunit) in the ventral tegmental area (VTA), a nucleus containing mesolimbic DA neurons. In contrast, chronic cocaine treatment did not alter levels of GluR2 (an AMPA receptor subunit), NMDA2A/B (NMDA receptor subunits), or GluR6/7 (kainate receptor subunits) in this brain region. Moreover, GluR1 and NMDAR1 levels were not regulated in other regions of the mesolimbic or nigrostriatal DA pathways, including the substantia nigra. Because several drugs of abuse and stress can elicit common and cross-sensitizing effects on mesolimbic DA function, we next examined whether repeated morphine and stress treatments would regulate these proteins similarly in the VTA. Although morphine delivered by subcutaneous pellet implantation had no significant effect on subunit levels, morphine delivered intermittently by subcutaneous injections of escalating doses elevated GluR1 levels in the VTA. Repeated restraint stress also increased GluR1 levels in the VTA, whereas an unpredictable stress paradigm (2 stressors/d under variable conditions) increased both GluR1 and NMDAR1 levels in this brain region. Unlike cocaine, morphine, and stress, repeated treatment with other psychotropic drugs (haloperidol, raclopride, sertraline, and desipramine) that lack reinforcing or sensitizing properties did not regulate GluR1 or NMDAR1 subunit levels in the VTA. increased glutamate receptor subunit expression in the VTA may represent an important molecular mechanism by which drugs of abuse and stress exert common, long-term effects on mesolimbic DA function.
    BibTeX:
    @article{Fitzgerald1996,
      author = {Fitzgerald, LW and Ortiz, J and Hamedani, AG and Nestler, EJ},
      title = {Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: Common adaptations among cross-sensitizing agents},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1996},
      volume = {16},
      number = {1},
      pages = {274-282}
    }
    
    Floresco, S., Seamans, J. & Phillips, A. Selective roles for hippocampal, prefrontal cortical, and ventral striatal circuits in radial-arm maze tasks with or without a delay {1997} JOURNAL OF NEUROSCIENCE
    Vol. {17}({5}), pp. {1880-1890} 
    article  
    Abstract: The hippocampus, the prefrontal cortex, and the ventral striatum form interconnected neural circuits that may underlie aspects of spatial cognition and memory. In the present series of experiments, we investigated functional interactions between these areas in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. The two-phase delayed task consisted of a training phase that provided rats with information about where food would be located on the maze 30 min later during a test phase. The single-phase nondelayed task was identical to the test phase of the delayed task, but in the absence of a training phase rats lacked previous knowledge of the location of food on the maze. Transient inactivation of the ventral CA1/subiculum (vSub) by a bilateral injection of lidocaine disrupted performance on both tasks. Lidocaine injections into the vSub on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task but not the nondelayed task. Transient disconnections between the vSub and the nucleus accumbens produced the opposite effect, disrupting foraging during the nondelayed task but not during the delayed task. These data suggest that serial transmission of information between the vSub and the prefrontal cortex is required when trial-unique, short-term memory is used to guide prospective search behavior. In contrast, exploratory goal-directed locomotion in a novel situation not requiring previously acquired information about the location of food is dependent on serial transmission between the hippocampus and the nucleus accumbens. These results indicate that different aspects of spatially mediated behavior are subserved by separate, distributed limbic-cortical-striatal networks.
    BibTeX:
    @article{Floresco1997,
      author = {Floresco, SB and Seamans, JK and Phillips, AG},
      title = {Selective roles for hippocampal, prefrontal cortical, and ventral striatal circuits in radial-arm maze tasks with or without a delay},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1997},
      volume = {17},
      number = {5},
      pages = {1880-1890}
    }
    
    Floresco, S., West, A., Ash, B., Moore, H. & Grace, A. Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission {2003} NATURE NEUROSCIENCE
    Vol. {6}({9}), pp. {968-973} 
    article DOI  
    Abstract: The mesolimbic dopamine system is centrally involved in reward and goal-directed behavior, and it has been implicated in multiple psychiatric disorders. Understanding the mechanism by which dopamine participates in these activities requires comprehension of the dynamics of dopamine release. Here we report dissociable regulation of dopamine neuron discharge by two separate afferent systems in rats; inhibition of pallidal afferents selectively increased the population activity of dopamine neurons, whereas activation of pedunculopontine inputs increased burst firing. Only the increase in population activity increased ventral striatal dopamine efflux. After blockade of dopamine reuptake, however, enhanced bursting increased dopamine efflux three times more than did enhanced population activity. These results provide insight into multiple regulatory systems that modulate dopamine system function: burst firing induces massive synaptic dopamine release, which is rapidly removed by reuptake before escaping the synaptic cleft, whereas increased population activity modulates tonic extrasynaptic dopamine levels that are less influenced by reuptake.
    BibTeX:
    @article{Floresco2003,
      author = {Floresco, SB and West, AR and Ash, B and Moore, H and Grace, AA},
      title = {Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission},
      journal = {NATURE NEUROSCIENCE},
      year = {2003},
      volume = {6},
      number = {9},
      pages = {968-973},
      doi = {{10.1038/nn1103}}
    }
    
    FREMEAU, R., DUNCAN, G., FORNARETTO, M., DEARRY, A., GINGRICH, J., BREESE, G. & CARON, M. LOCALIZATION OF D1 DOPAMINE RECEPTOR MESSENGER-RNA IN BRAIN SUPPORTS A ROLE IN COGNITIVE, AFFECTIVE, AND NEUROENDOCRINE ASPECTS OF DOPAMINERGIC NEUROTRANSMISSION {1991} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {88}({9}), pp. {3772-3776} 
    article  
    Abstract: Expression of a D1 dopamine receptor was examined in the rat brain by using a combination of in situ hybridization and in vitro receptor autoradiography. Cells expressing D1 receptor mRNA were localized to many but not all, brain regions receiving dopaminergic innervation. The highest levels of hybridization were detected in the caudate-putamen, nucleus accumbens, and olfactory tubercle. Cells expressing D1 receptor mRNA were also detected throughout the cerebral cortex, limbic system, hypothalamus, and thalamus. D1 receptor mRNA was differentially expressed in distinct regions of the hippocampal formation. Dentate granule cells were labeled in dorsal but not ventral regions, whereas the subicular complex was prominently labeled in ventral but not dorsal regions. Intermediate to high levels of D1 binding sites, but no hybridizing D1 receptor mRNA, were detected in the substantia nigra pars reticulata, globus pallidus, entopeduncular nucleus, and subthalamic nucleus. In these brain regions, which are involved in the efferent flow of information from the basal ganglia, D1 receptors may be localized on afferent nerve terminals originating in other brain regions. These results indicate that in addition to a role in control of motor function, the D1 receptor may also participate in the cognitive, affective, and neuroendocrine effects of dopaminergic neurotransmission.
    BibTeX:
    @article{FREMEAU1991,
      author = {FREMEAU, RT and DUNCAN, GE and FORNARETTO, MG and DEARRY, A and GINGRICH, JA and BREESE, GR and CARON, MG},
      title = {LOCALIZATION OF D1 DOPAMINE RECEPTOR MESSENGER-RNA IN BRAIN SUPPORTS A ROLE IN COGNITIVE, AFFECTIVE, AND NEUROENDOCRINE ASPECTS OF DOPAMINERGIC NEUROTRANSMISSION},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1991},
      volume = {88},
      number = {9},
      pages = {3772-3776}
    }
    
    GARRIS, P., CIOLKOWSKI, E., PASTORE, P. & WIGHTMAN, R. EFFLUX OF DOPAMINE FROM THE SYNAPTIC CLEFT IN THE NUCLEUS-ACCUMBENS OF THE RAT-BRAIN {1994} JOURNAL OF NEUROSCIENCE
    Vol. {14}({10}), pp. {6084-6093} 
    article  
    Abstract: Synaptic release of dopamine in the nucleus accumbens of the intact rat brain elicited by a single electrical impulse applied to ascending dopaminergic fibers results in extracellular concentrations sufficient to bind the known dopamine receptors. The dopamine concentration observed after four rapid, sequential pulses is exactly four times greater and is unaffected by pharmacological antagonism of dopamine uptake and receptor sites at supramaximal concentrations. Thus, dopamine efflux from the synaptic cleft is not restricted by binding to intrasynaptic proteins on the time scale of the measurements (50-100 msec). The extracellular concentration, as a result of a single stimulus pulse, is 0.25 mu M and is rapidly removed by extrasynaptic uptake. This maximal, transient concentration of dopamine is 60 times higher than steady-state concentrations reported previously using dialysis techniques, illustrating that dopamine extracellular concentrations are spatially and temporally heterogenous. In contrast to ACh transmission at the neuromuscular junction, the dopamine synapse in the telencephalon is designed for the effective efflux of dopamine from the synaptic cleft to the extrasynaptic compartment during neurotransmission.
    BibTeX:
    @article{GARRIS1994,
      author = {GARRIS, PA and CIOLKOWSKI, EL and PASTORE, P and WIGHTMAN, RM},
      title = {EFFLUX OF DOPAMINE FROM THE SYNAPTIC CLEFT IN THE NUCLEUS-ACCUMBENS OF THE RAT-BRAIN},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1994},
      volume = {14},
      number = {10},
      pages = {6084-6093}
    }
    
    GARRIS, P. & WIGHTMAN, R. DIFFERENT KINETICS GOVERN DOPAMINERGIC TRANSMISSION IN THE AMYGDALA, PREFRONTAL CORTEX, AND STRIATUM - AN IN-VIVO VOLTAMMETRIC STUDY {1994} JOURNAL OF NEUROSCIENCE
    Vol. {14}({1}), pp. {442-450} 
    article  
    Abstract: The regulation of extracellular dopamine (DA) concentrations was examined and compared in vivo in four projection fields of mesotelencephalic dopaminergic neurons with fast-scan cyclic voltammetry at carbon-fiber microelectrodes. Transient electrical stimulation of ascending DA fibers in a near physiological range of frequencies (10-20 Hz) elicited similar levels of extracellular DA in the medial prefrontal cortex (MPFC), basal lateral amygdaloid nucleus (BAN), caudate-putamen (CP), and nucleus accumbens (NAc) despite the documented 90-fold disparity in DA tissue levels and terminal density. However, marked differences were observed in the dynamics and overall frequency dependence of the evoked synaptic overflow of DA. These differences are due to the significantly different rates of release and uptake found in each of the four regions. For example, rate constants for the release and uptake of DA were similar in the MPFC and BAN but approximately 8 and 50 times less, respectively, than that in the CP and NAc. When the parameters were normalized to endogenous DA tissue content, a unique picture emerged: compared to all other regions, relative release was 10-fold greater in the MPFC while relative uptake was at least 10 times less in the BAN. The results further differentiate the functional characteristics of mesotelencephalic dopaminergic systems and demonstrate the regiospecific nature of DA neural transmission in the brain. In addition, the regulation of extracellular DA levels in the MPFC and BAN is suitable for the `'long-range'' transfer of chemical information in the brain and is consistent with a hypothesis of extrasynaptic neurotransmission.
    BibTeX:
    @article{GARRIS1994a,
      author = {GARRIS, PA and WIGHTMAN, RM},
      title = {DIFFERENT KINETICS GOVERN DOPAMINERGIC TRANSMISSION IN THE AMYGDALA, PREFRONTAL CORTEX, AND STRIATUM - AN IN-VIVO VOLTAMMETRIC STUDY},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1994},
      volume = {14},
      number = {1},
      pages = {442-450}
    }
    
    Gerdeman, G., Partridge, J., Lupica, C. & Lovinger, D. It could be habit forming: drugs of abuse and striatal synaptic plasticity {2003} TRENDS IN NEUROSCIENCES
    Vol. {26}({4}), pp. {184-192} 
    article DOI  
    Abstract: Drug addiction can take control of the brain and behavior, activating behavioral patterns that are directed excessively and compulsively toward drug usage. Such patterns often involve the development of repetitive and nearly automatic behaviors that we call habits. The striatum, a subcortical brain region important for proper motor function as well as for the formation of behavioral habits, is a major target for drugs of abuse. Here, we review recent studies of long-term synaptic plasticity in the striatum, emphasizing that drugs of abuse can exert pronounced influences on these processes, both in the striatum and in the dopaminergic midbrain. Synaptic plasticity in the ventral striatum appears to play a prominent role in early stages of drug use, whereas dopamine- and endocannabinoid-dependent synaptic plasticity in the dorsal striatum could contribute to the formation of persistent drug-related habits when casual drug use progresses towards compulsive drug use and addiction.
    BibTeX:
    @article{Gerdeman2003,
      author = {Gerdeman, GL and Partridge, JG and Lupica, CR and Lovinger, DM},
      title = {It could be habit forming: drugs of abuse and striatal synaptic plasticity},
      journal = {TRENDS IN NEUROSCIENCES},
      year = {2003},
      volume = {26},
      number = {4},
      pages = {184-192},
      doi = {{10.1016/S0166-2236(03)00065-1}}
    }
    
    Giros, B., Jaber, M., Jones, S., Wightman, R. & Caron, M. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter {1996} NATURE
    Vol. {379}({6566}), pp. {606-612} 
    article  
    Abstract: Disruption of the mouse dopamine transporter gene results in spontaneous hyperlocomotion despite major adaptive changes, such as decreases in neurotransmitter and receptor levels. In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission. The dopamine transporter is an obligatory target of cocaine and amphetamine, as these psychostimulants have no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter.
    BibTeX:
    @article{Giros1996,
      author = {Giros, B and Jaber, M and Jones, SR and Wightman, RM and Caron, MG},
      title = {Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter},
      journal = {NATURE},
      year = {1996},
      volume = {379},
      number = {6566},
      pages = {606-612}
    }
    
    GOEDERS, N., LANE, J. & SMITH, J. SELF-ADMINISTRATION OF METHIONINE ENKEPHALIN INTO THE NUCLEUS ACCUMBENS {1984} PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
    Vol. {20}({3}), pp. {451-455} 
    article  
    BibTeX:
    @article{GOEDERS1984,
      author = {GOEDERS, NE and LANE, JD and SMITH, JE},
      title = {SELF-ADMINISTRATION OF METHIONINE ENKEPHALIN INTO THE NUCLEUS ACCUMBENS},
      journal = {PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR},
      year = {1984},
      volume = {20},
      number = {3},
      pages = {451-455}
    }
    
    Goldstein, L., Rasmusson, A., Bunney, B. & Roth, R. Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat {1996} JOURNAL OF NEUROSCIENCE
    Vol. {16}({15}), pp. {4787-4798} 
    article  
    Abstract: Exposure to mild stress is known to activate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) metabolism in the anteromedial prefrontal cortex (m-PFC). Neuroanatomical site(s) providing afferent control of the stress activation of the m-PFC monoaminergic systems is at present unknown. The present study used a conditioned stress model in which rats were trained to fear a substartle-threshold tone paired previously with footshock and assessed for behavioral, neuroendocrine, and neurochemical stress responses. Bilateral NMDA-induced excitotoxic lesioning of the basolateral and central nuclei of the amygdala was performed before or after training. Pretraining amygdala lesions blocked stress-induced freezing behavior, ultrasonic vocalizations, adrenocortical activation, and dopaminergic metabolic activation in the m-PFC. Post-training amygdala lesions blocked stress-induced m-PFC DA, 5-HT, and NE metabolic activation. Post-training amygdala lesions also blocked stress-induced freezing and defecation, and greatly attenuated adrenocortical activation, These data provide evidence of amygdalar control of stress-induced metabolic activation of the monoaminergic systems in the m-PFC, as well as amygdalar integration of behavioral and neuroendocrine components of the rat stress response. These results are discussed in terms of possible relevance to stress-induced exacerbation of schizophrenic symptoms and the pathophysiology of posttraumatic stress disorder.
    BibTeX:
    @article{Goldstein1996,
      author = {Goldstein, LE and Rasmusson, AM and Bunney, BS and Roth, RH},
      title = {Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1996},
      volume = {16},
      number = {15},
      pages = {4787-4798}
    }
    
    Goldstein, R. & Volkow, N. Drug addiction and its underlying neurobiological basis: Neuroimaging evidence for the involvement of the frontal cortex {2002} AMERICAN JOURNAL OF PSYCHIATRY
    Vol. {159}({10}), pp. {1642-1652} 
    article  
    Abstract: Objective: Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. Method: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroirnaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. Results: The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to track, update, and modulate the salience of a reinforcer as a function of context and expectation and the ability to control and inhibit prepotent responses. Conclusions: These results imply that addiction connotes cortically regulated cognitive and emotional processes, which result in the overvaluing of drug reinforcers, the undervaluing of alternative reinforcers, and deficits in inhibitory control for drug responses. These changes in addiction, which the authors call I-RISA (impaired response inhibition and salience attribution), expand the traditional concepts of drug dependence that emphasize limbic-regulated responses to pleasure and reward.
    BibTeX:
    @article{Goldstein2002,
      author = {Goldstein, RZ and Volkow, ND},
      title = {Drug addiction and its underlying neurobiological basis: Neuroimaging evidence for the involvement of the frontal cortex},
      journal = {AMERICAN JOURNAL OF PSYCHIATRY},
      year = {2002},
      volume = {159},
      number = {10},
      pages = {1642-1652}
    }
    
    GOVONI, S., HONG, J., YANG, H. & COSTA, E. INCREASE OF NEUROTENSIN CONTENT ELICITED BY NEUROLEPTICS IN NUCLEUS ACCUMBENS {1980} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {215}({2}), pp. {413-417} 
    article  
    BibTeX:
    @article{GOVONI1980,
      author = {GOVONI, S and HONG, JS and YANG, HYT and COSTA, E},
      title = {INCREASE OF NEUROTENSIN CONTENT ELICITED BY NEUROLEPTICS IN NUCLEUS ACCUMBENS},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1980},
      volume = {215},
      number = {2},
      pages = {413-417}
    }
    
    Grace, A. Gating of information flow within the limbic system and the pathophysiology of schizophrenia {2000} BRAIN RESEARCH REVIEWS
    Vol. {31}({2-3}), pp. {330-341} 
    article  
    Abstract: Although first thought of as a dopaminergic disorder, there is little direct evidence to support a primary pathology in the dopamine system as the etiological factor in schizophrenia. In contrast, evidence is amassing in support of a cortical disturbance in this disorder; one consequence of which is a disruption in the cortical regulation of subcortical dopamine systems. Our studies show that the hippocampus plays a major role in this interaction, in that, along with the dopamine system, it provides a gating influence over information Row from the prefrontal cortex at the level of the nucleus accumbens. Moreover, chemically-induced disruption of the development of the hippocampus and entorhinal cortex were found to lead to pathophysiological changes in these interactions in the limbic system of adult rats. Therefore, schizophrenia is proposed to be a developmentally-related disorder, in which disruption of the hippocampal influence over the limbic system during ontogeny results in a pathological alteration of corticoaccumbens interactions in the adult organism. (C) 2000 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{Grace2000,
      author = {Grace, AA},
      title = {Gating of information flow within the limbic system and the pathophysiology of schizophrenia},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {2000},
      volume = {31},
      number = {2-3},
      pages = {330-341},
      note = {Nobel Symposium 111: Schizophrenia - Pathophysiological Mechanisms, STOCKHOLM, SWEDEN, OCT 01-03, 1998}
    }
    
    Granon, S., Passetti, F., Thomas, K., Dalley, J., Everitt, B. & Robbins, T. Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex {2000} JOURNAL OF NEUROSCIENCE
    Vol. {20}({3}), pp. {1208-1215} 
    article  
    Abstract: The role in spatial divided and sustained attention of D1 and D2-like dopamine (DA) receptors in the rat prelimbic medial prefrontal cortex (mPFC) was investigated in a five-choice serial reaction time task. Rats were trained to detect brief flashes of light (0.5-0.25 sec) presented randomly in a spatial array of five apertures. When performance stabilized, animals received bilateral microinfusions of either the D1 DA receptor antagonist SCH 23390, the D1 DA receptor agonist SKF 38393, or the D2 DA antagonist sulpiride into the mPFC. Rats were divided into two groups, with low (<75% correct) and high (>75 baseline levels of accuracy. Infusions of the D2 receptor antagonist sulpiride had no significant effect on any task variable. SCH 23390 (0.3 mu g) selectively impaired the accuracy of attentional performance in rats in the high baseline condition. By contrast, SKF 38393 (0.06 mu g) enhanced the accuracy of attentional performance in the low baseline condition, a lower dose (0.03 mu g) also increasing the speed of making correct responses. Finally, the beneficial effects of SKF-383893 on choice accuracy were antagonized by SCH 23390 (1.0 mu g). The results provide apparently the first demonstration of enhanced cognitive function after local administration of a D1 receptor agonist to the mPFC and suggest dissociable roles of D1 and D2 DA receptors of the mPFC in modulating attentional function.
    BibTeX:
    @article{Granon2000,
      author = {Granon, S and Passetti, F and Thomas, KL and Dalley, JW and Everitt, BJ and Robbins, TW},
      title = {Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2000},
      volume = {20},
      number = {3},
      pages = {1208-1215}
    }
    
    GRAY, J., FELDON, J., RAWLINS, J., SMITH, A. & HEMSLEY, D. THE NEUROPSYCHOLOGY OF SCHIZOPHRENIA {1991} BEHAVIORAL AND BRAIN SCIENCES
    Vol. {14}({1}), pp. {1-19} 
    article  
    Abstract: A model is proposed for integrating the neural and cognitive aspects of the positive symptoms of acute schizophrenia using evidence from: postmortem neuropathology and neurochemistry, clinical and preclinical studies of dopaminergic neurotransmission, anatomical connections between the limbic system and the basal ganglia, attentional and other cognitive abnormalities underlying the positive symptoms of schizophrenia, specific animal models of some of these abnormalities, and previous attempts to model the cognitive functions of the spetohippocampal system and the motor functions of the basal ganglia. Anatomically, the model emphasises the projections from the septohippocampal system, via the subiculum and the amygdala to nucleus accumbens and their interaction with the ascending dopaminergic projection to the accumbens. Psychologically, the model emphasizes a failure in schizophrenia to integrate stored memories of past regularieties of perceptual input with ongoing motor programs in the control of current perception. A number of recent experiments that offer support for the model are fully described, including anatomical studies of limbic-striatal connections, studies in the rat of the effects of damage to these connections and of the effects of amphetamine and neuroleptics on the partial reinforcement extinction effect, latent inhibition and the Kamin blocking effect, and studies of the latter two phenomena in acuate and chronic schizophrenics.
    BibTeX:
    @article{GRAY1991,
      author = {GRAY, JA and FELDON, J and RAWLINS, JNP and SMITH, AD and HEMSLEY, DR},
      title = {THE NEUROPSYCHOLOGY OF SCHIZOPHRENIA},
      journal = {BEHAVIORAL AND BRAIN SCIENCES},
      year = {1991},
      volume = {14},
      number = {1},
      pages = {1-19}
    }
    
    Grimm, J., Lu, L., Hayashi, T., Hope, B., Su, T. & Shaham, Y. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: Implications for incubation of cocaine craving {2003} JOURNAL OF NEUROSCIENCE
    Vol. {23}({3}), pp. {742-747} 
    article  
    Abstract: Using a rat model of drug craving, we found that the responsiveness to cocaine cues progressively increases or incubates over the first 60 d of cocaine withdrawal. Here we studied whether alterations in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system are associated with this incubation phenomenon. BDNF is involved in synaptic plasticity and was found to enhance responding for cues associated with natural rewards. Rats were trained to press a lever to receive intravenous cocaine or oral sucrose for 6 hr/d for 10 d; each earned reward was paired with a tone-light cue. Resumption of lever-pressing behavior was then assessed on days 1, 30, or 90 of reward withdrawal. First, resistance to extinction was assessed during 6 hr in which lever presses were not reinforced and the cue was absent. Second, cue-induced reinstatement was assessed after extinction during 1 hr in which responding led to cue presentations. Other rats were killed without testing on days 1, 30, and 90 of reward withdrawal, and BDNF and nerve growth factor (NGF) protein levels were measured in the ventral tegmental area (VTA), accumbens, and amygdala. Lever pressing during extinction and cue-induced reinstatement tests of cocaine craving progressively increased after cocaine withdrawal. Time-dependent changes also were observed during the tests for sucrose craving, with maximal responding on day 30. BDNF, but not NGF, levels in the VTA, accumbens, and amygdala progressively increased after cocaine, but not sucrose, withdrawal. Time-dependent increases in BDNF levels may lead to synaptic modifications that underlie enhanced responsiveness to cocaine cues after prolonged withdrawal periods.
    BibTeX:
    @article{Grimm2003,
      author = {Grimm, JW and Lu, L and Hayashi, T and Hope, BT and Su, TP and Shaham, Y},
      title = {Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: Implications for incubation of cocaine craving},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2003},
      volume = {23},
      number = {3},
      pages = {742-747}
    }
    
    GROENEWEGEN, H., BERENDSE, H., WOLTERS, J. & LOHMAN, A. THE ANATOMICAL RELATIONSHIP OF THE PREFRONTAL CORTEX WITH THE STRIATOPALLIDAL SYSTEM, THE THALAMUS AND THE AMYGDALA - EVIDENCE FOR A PARALLEL ORGANIZATION {1990} PROGRESS IN BRAIN RESEARCH
    Vol. {85}, pp. {95-118} 
    article  
    Abstract: Recent findings in primates indicate that the connections of the frontal lobe, the basal ganglia, and the thalamus are organized in a number of parallel, functionally segregated circuits. In the present account, we have focused on the organization of the connections between the prefrontal cortex, the basal ganglia and the mediodorsal thalamic nucleus in the rat. It is concluded that in this species, in analogy with the situation in primates, a number of parallel basal ganglia-thalamocortical circuits exist. Furthermore, data are presented indicating that the projections from particular parts of the amygdala and from individual nuclei of he midline and intralaminar thalamic complex to the prefrontal cortex and the striatum are in register with the arrangements in the parallel circuits. These findings emphasize that the functions of the different subregions of the prefrontal cortex cannot be considered separately but must be viewed as components of the integrative functions of the circuits in which they are involved.
    BibTeX:
    @article{GROENEWEGEN1990,
      author = {GROENEWEGEN, HJ and BERENDSE, HW and WOLTERS, JG and LOHMAN, AHM},
      title = {THE ANATOMICAL RELATIONSHIP OF THE PREFRONTAL CORTEX WITH THE STRIATOPALLIDAL SYSTEM, THE THALAMUS AND THE AMYGDALA - EVIDENCE FOR A PARALLEL ORGANIZATION},
      journal = {PROGRESS IN BRAIN RESEARCH},
      year = {1990},
      volume = {85},
      pages = {95-118}
    }
    
    GROENEWEGEN, H. & RUSSCHEN, F. ORGANIZATION OF THE EFFERENT PROJECTIONS OF THE NUCLEUS ACCUMBENS TO PALLIDAL, HYPOTHALAMIC, AND MESENCEPHALIC STRUCTURES - A TRACING AND IMMUNOHISTOCHEMICAL STUDY IN THE CAT {1984} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {223}({3}), pp. {347-367} 
    article  
    BibTeX:
    @article{GROENEWEGEN1984,
      author = {GROENEWEGEN, HJ and RUSSCHEN, FT},
      title = {ORGANIZATION OF THE EFFERENT PROJECTIONS OF THE NUCLEUS ACCUMBENS TO PALLIDAL, HYPOTHALAMIC, AND MESENCEPHALIC STRUCTURES - A TRACING AND IMMUNOHISTOCHEMICAL STUDY IN THE CAT},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1984},
      volume = {223},
      number = {3},
      pages = {347-367}
    }
    
    Groenewegen, H., Wright, C., Beijer, A. & Voorn, P. Convergence and segregation of ventral striatal inputs and outputs {1999}
    Vol. {877}ADVANCING FROM THE VENTRAL STRIATUM TO THE EXTENDED AMYGDALA - IMPLICATIONS FOR NEUROPSYCHIATRY AND DRUG ABUSE: IN HONOR OF LENNART HEIMER , pp. {49-63} 
    inproceedings  
    Abstract: The ventral striatum, which prominently includes the nucleus accumbens (Acb), is a heterogeneous area. Within the Acb of rats, a peripherally located shell and a centrally situated core can be recognized that have different connectional, neurochemical, and functional identities. Although the Acb core resembles in many respects the dorsally adjacent caudate-putamen complex in its striatal character, the Acb shell has, in addition to striatal features, a more diverse array of neurochemical characteristics, and afferent and efferent connections. Inputs and outputs of the Acb, in particular of the shell, are inhomogeneously distributed, resulting in a mosaical arrangement of concentrations of afferent fibers and terminals and clusters of output neurons. To determine the precise relationships between the distributional patterns of various afferents (e.g., from the prefrontal cortex, the basal amygdaloid complex, the hippocampal formation, and the midline/intralaminar thalamic nuclei) and efferents to the ventral pallidum and mesencephalon, neuroanatomical anterograde and retrograde tracing experiments were carried out. The results of the double anterograde, double retrograde, and anterograde/retrograde tracing experiments indicate that various parts of the shell (dorsomedial, ventromedial, ventral, and lateral) and the core (medial and lateral) have different input-output characteristics. Furthermore, within these Acb regions, various populations of neurons can be identified, arranged in a cluster-like fashion, onto which specific sets of afferents converge and that project to particular output stations, distinct from the input-output relationships of neighboring, clusterlike neuronal populations. These results support the idea that the nucleus accumbens may consist of a collection of neuronal ensembles with different input-output relationships and, presumably, different functional characteristics.
    BibTeX:
    @inproceedings{Groenewegen1999,
      author = {Groenewegen, HJ and Wright, CI and Beijer, AVJ and Voorn, P},
      title = {Convergence and segregation of ventral striatal inputs and outputs},
      booktitle = {ADVANCING FROM THE VENTRAL STRIATUM TO THE EXTENDED AMYGDALA - IMPLICATIONS FOR NEUROPSYCHIATRY AND DRUG ABUSE: IN HONOR OF LENNART HEIMER },
      year = {1999},
      volume = {877},
      pages = {49-63},
      note = {Conference on Advancing from the Ventral Striatum to the Extended Amygdala - Implications for Neuropsychiatry and Drug Abuse-In Honor of Lennart Heimer, CHARLOTTESVILLE, VIRGINIA, OCT 18-21, 1998}
    }
    
    Guillin, O., Diaz, J., Carroll, P., Griffon, N., Schwartz, J. & Sokoloff, P. BDNF controls dopamine D-3 receptor expression and triggers behavioural sensitization {2001} NATURE
    Vol. {411}({6833}), pp. {86-89} 
    article  
    Abstract: Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body(1). A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely(2,3), is released on neuron depolarization(1), and triggers rapid intracellular signals(4) and action potentials in central neurons(5). Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D-3 receptor in nucleus accumbens(6-8) both during development and in adulthood. BDNF from corticostriatal neurons(3) also induces behavioural sensitization, by triggering overexpression of the D-3 receptor in striatum of hemiparkinsonian rats(9). Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction(10), schizophrenia(11) or Parkinson's disease(12), in which D-3 receptor expression is abnormal.
    BibTeX:
    @article{Guillin2001,
      author = {Guillin, O and Diaz, J and Carroll, P and Griffon, N and Schwartz, JC and Sokoloff, P},
      title = {BDNF controls dopamine D-3 receptor expression and triggers behavioural sensitization},
      journal = {NATURE},
      year = {2001},
      volume = {411},
      number = {6833},
      pages = {86-89}
    }
    
    HABER, S., KUNISHIO, K., MIZOBUCHI, M. & LYNDBALTA, E. THE ORBITAL AND MEDIAL PREFRONTAL CIRCUIT THROUGH THE PRIMATE BASAL GANGLIA {1995} JOURNAL OF NEUROSCIENCE
    Vol. {15}({7, Part 1}), pp. {4851-4867} 
    article  
    Abstract: The ventral striatum is considered an interface between limbic and motor systems, We followed the orbital and medial prefrontal circuit through the monkey basal ganglia by analyzing the projection from this cortical area to the ventral striatum and the representation of orbitofrontal cortex via the striatum, in the globus pallidus and substantia nigra. Following injections of Lucifer yellow and horse radish peroxidase into the medial ventral striatum, there is a very densely labeled distribution of cells in areas 13a and 13b, primarily in layers V and VI, and in medial prefrontal areas 32 and 25, Injections into the shell of the nucleus accumbens labeled primarily areas 25 and 32. The reaction product in the globus pallidus and the substantia nigra supports previous studies demonstrating that efferent projections from the ventral striatum are represented topographically in the ventral pallidum and non-topographically in the substantia nigra, pars compacta. Tritiated amino acid or PHA-L tracer injections into orbitofrontal cortex produce dense patches of terminal labeling along the medial edge of the caudate nucleus and the dorsal part of the nucleus accumbens. These results demonstrate that the orbital prefrontal cortex projects primarily to the medial edge of the ventral striatum and to the core of the nucleus accumbens, The arrangement of terminals in the globus pallidus and substantia nigra show two different patterns. Thus, the orbital and medial prefrontal cortex is represented in a confined region of the globus pallidus but throughout an extensive area of the dorsal substantia nigra, Terminals are extensive throughout the region of the dopaminergic neurons, suggesting that this input may influence a wide area of both the striatum and frontal cortex.
    BibTeX:
    @article{HABER1995,
      author = {HABER, SN and KUNISHIO, K and MIZOBUCHI, M and LYNDBALTA, E},
      title = {THE ORBITAL AND MEDIAL PREFRONTAL CIRCUIT THROUGH THE PRIMATE BASAL GANGLIA},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1995},
      volume = {15},
      number = {7, Part 1},
      pages = {4851-4867}
    }
    
    Harris, G., Wimmer, M. & Aston-Jones, G. A role for lateral hypothalamic orexin neurons in reward seeking {2005} NATURE
    Vol. {437}({7058}), pp. {556-559} 
    article DOI  
    Abstract: The lateral hypothalamus is a brain region historically implicated in reward and motivation(1 - 4), but the identity of the neurotransmitters involved are unknown. The orexins ( or hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons(5,6). Although knockout and transgenic overexpression studies have implicated orexin neurons in arousal and sleep(7), these cells also project to reward- associated brain regions, including the nucleus accumbens and ventral tegmental area(8,9). This indicates a possible role for these neurons in reward function and motivation(3,10), consistent with previous studies implicating these neurons in feeding(6). Here we show that activation of lateral hypothalamus orexin neurons is strongly linked to preferences for cues associated with drug and food reward. In addition, we show that chemical activation of lateral hypothalamus orexin neurons reinstates an extinguished drug- seeking behaviour. This reinstatement effect was completely blocked by prior administration of an orexin A antagonist. Moreover, administration of the orexin A peptide directly into the ventral tegmental area also reinstated drug- seeking. These data reveal a new role for lateral hypothalamus orexin neurons in reward- seeking, drug relapse and addiction.
    BibTeX:
    @article{Harris2005,
      author = {Harris, GC and Wimmer, M and Aston-Jones, G},
      title = {A role for lateral hypothalamic orexin neurons in reward seeking},
      journal = {NATURE},
      year = {2005},
      volume = {437},
      number = {7058},
      pages = {556-559},
      doi = {{10.1038/nature04071}}
    }
    
    Harrison, A., Everitt, B. & Robbins, T. Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms {1997} PSYCHOPHARMACOLOGY
    Vol. {133}({4}), pp. {329-342} 
    article  
    Abstract: A series of ten experiments examined the effects of profound central 5-HT depletion on attentional performance in the rat in the five-choice serial reaction time task, and also determined the effects of such depletion on responding affected by d-amphetamine and by selective dopamine receptor antagonists. Rats were trained to detect and locate brief visual stimuli randomly presented in one of five spatial locations. When performance had stabilised (> 80% correct, < 20% omissions), selective central 5-HT depletion was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. The lesioned animals performed the five-choice serial reaction time task with the same degree of accuracy as the sham-operated controls. However, 5-HT depletion reduced the percentage of omitted trials and increased the number of premature/anticipatory responses. This pattern of behaviour following 5-HT depletion could not be attributed to enhanced primary motivation as demonstrated by measures of food intake and latencies to collect food reinforcement. The lesion attenuated the increase of premature responding induced by high doses of systemically administered d-amphetamine. 5-HT depletion also attenuated the dose-dependent decrease in accuracy induced by (-)-sulpiride, a D-2 receptor antagonist, although the effects of this drug on response latencies and premature responding were similar in both groups. However, the systemic administration of the D-1 receptor antagonist, SCH 23390, blocked the impulsive responding produced by the lesion as indicated by a lack of lesion effects on the percentage of omitted trials and premature responding. The results suggest that central 5-HT depletion results in impulsive, fast responding, which nevertheless does not impair accuracy of visual discrimination performance. The increased impulsivity may be mediated by altered 5-HT-dopamine interactions, with the lesion removing an inhibitory influence over dopamine neurotransmission.
    BibTeX:
    @article{Harrison1997,
      author = {Harrison, AA and Everitt, BJ and Robbins, TW},
      title = {Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1997},
      volume = {133},
      number = {4},
      pages = {329-342}
    }
    
    HARRO, J., VASAR, E. & BRADWEJN, J. CCK IN ANIMAL AND HUMAN RESEARCH ON ANXIETY {1993} TRENDS IN PHARMACOLOGICAL SCIENCES
    Vol. {14}({6}), pp. {244-249} 
    article  
    Abstract: Much data has accumulated over the past decade supporting the hypothesis that CCK plays a role in the neurobiology of anxiety and panic attacks. These data originated from animal studies and human studies that were initiated independently, but the conclusions are remarkably consistent. In this review, Jacques Bradwejn and colleagues examine the evidence for a role of CCK in anxiety and panic attacks, and highlight the consistencies between animal and human studies.
    BibTeX:
    @article{HARRO1993,
      author = {HARRO, J and VASAR, E and BRADWEJN, J},
      title = {CCK IN ANIMAL AND HUMAN RESEARCH ON ANXIETY},
      journal = {TRENDS IN PHARMACOLOGICAL SCIENCES},
      year = {1993},
      volume = {14},
      number = {6},
      pages = {244-249}
    }
    
    Heimer, L., Alheid, G., deOlmos, J., Groenewegen, H., Haber, S., Harlan, R. & Zahm, D. The accumbens: Beyond the core-shell dichotomy {1997} JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES
    Vol. {9}({3}), pp. {354-381} 
    article  
    Abstract: This article highlights recent discoveries related to the accumbens and closely associated structures, with special reference to their importance in neuropsychiatry. The development of `'striatal patches'' in the accumbens is reviewed in a series of pictures. Neuronal ensembles are discussed as potentially important functional-anatomical units. Attention is also drawn to recent discoveries related to the neuronal circuits that the primate accumbens establishes with the mesencephalic dopamine system. On the basis of histological and neurochemical differences, the accumbens has been divided into core and shell compartments. In the context of this article, the shell, which is an especially diversified part of the accumbens, is the subject of special attention because of its close relation to the extended amygdala and distinctive response to antipsychotic and psychoactive drugs.
    BibTeX:
    @article{Heimer1997,
      author = {Heimer, L and Alheid, GF and deOlmos, JS and Groenewegen, HJ and Haber, SN and Harlan, RE and Zahm, DS},
      title = {The accumbens: Beyond the core-shell dichotomy},
      journal = {JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES},
      year = {1997},
      volume = {9},
      number = {3},
      pages = {354-381}
    }
    
    HEIMER, L., ZAHM, D., CHURCHILL, L., KALIVAS, P. & WOHLTMANN, C. SPECIFICITY IN THE PROJECTION PATTERNS OF ACCUMBAL CORE AND SHELL IN THE RAT {1991} NEUROSCIENCE
    Vol. {41}({1}), pp. {89-125} 
    article  
    Abstract: The efferent projections of the core and shell areas of the nucleus accumbens were studied with a combination of anterograde and retrograde tract-tracing methods, including Phaseolus vulgaris-leucoagglutinin, horseradish peroxidase and fluorescent tracers. Both the core and shell regions project to pallidal areas, i.e. ventral pallidum and entopeduncular nucleus, with a distinct topography in the sense that the core projection is located in the dorsolateral part of ventral pallidum, whereas the shell projects to the medial part of the subcommissural ventral pallidum. Both regions of the accumbens also project to mesencephalon with a bias for the core projection to innervate the substantia nigra-lateral mesencephalic tegmentum, and for the shell projection to reach primarily the ventral tegmental-paramedian tegmentum area. The most pronounced differences between core and shell projections exist in regard to the hypothalamus and extended amygdala. Whereas the core projects primarily to the entopeduncular nucleus including a part that invades the lateral hypothalamus, the shell, in addition, projects diffusely throughout the rostrocaudal extent of the lateral hypothalamus as well as to the extended amygdala, especially its sublenticular part. Both the core and shell of the accumbens have unmistakable striatal characteristics both histologically and in their connectional patterns. The shell, however, has additional features that are reminiscent of the recently described extended amygdala [Alheid G. F. and Heimer L. (1988) Neuroscience 27, 1-39; de Olmos J. S. et al. (1985) In The Rat Nervous System, pp. 223-334]; in fact, the possibility exists that the shell represents a transitional zone that seems to characterize most of the fringes of the striatal complex, where it adjoins the extended amygdala.
    BibTeX:
    @article{HEIMER1991,
      author = {HEIMER, L and ZAHM, DS and CHURCHILL, L and KALIVAS, PW and WOHLTMANN, C},
      title = {SPECIFICITY IN THE PROJECTION PATTERNS OF ACCUMBAL CORE AND SHELL IN THE RAT},
      journal = {NEUROSCIENCE},
      year = {1991},
      volume = {41},
      number = {1},
      pages = {89-125}
    }
    
    Hemby, S., Co, C., Koves, T., Smith, J. & Dworkin, S. Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat {1997} PSYCHOPHARMACOLOGY
    Vol. {133}({1}), pp. {7-16} 
    article  
    Abstract: Studies indicate that nucleus accumbens (NAcc) dopamine neurotransmission is involved in the reinforcing and direct effects of cocaine. The present study was initiated to explore further the relationship of NAcc extracellular dopamine concentrations ([DA](e)) and cocaine self-administration using a yoked littermate design, Tn the first experiment, one rat from each litter was trained to self-administer cocaine IV (SA; 0.33 mg/inf) under a fixed ratio 2 schedule, while a second rat received simultaneous infusions of cocaine yoked to the infusions of the SA (YC), NAcc [DA](e) and cocaine concentrations ([COC]) were assessed during the test sessions using in vivo microdialysis combined with microbore HPLC procedures. [DA](e) and [COG] were significantly elevated in the SA and YC groups during the self-administration session; however, [DA](e) were greater in the SA group compared to the YC group in the first hour of the session, even though [COC] were not significantly different. On the following day, the rats previously allowed to self-administer cocaine were administered response-independent cocaine infusions yoked to the infusion pattern from the previous day. [DA](e) were significantly elevated above baseline levels during the session but were significantly less than concentrations obtained when cocaine was self-administered by these subjects. [COG] during the sessions were not significantly different between the two days. Baseline [DA](e) were not significantly different between the SA and YC groups or between Day 1 and Day 2. Furthermore, there was no significant difference in the in vitro probe recovery between one and two days following probe implantation. These results suggest that the context in which cocaine was administered significantly altered the neurochemical response to equivalent brain concentrations of cocaine. NAcc [DA](e) was significantly increased when the delivery of cocaine infusions was contingent on the behavior of the rat, indicative of a role in the neural processes underlying cocaine reinforcement.
    BibTeX:
    @article{Hemby1997,
      author = {Hemby, SE and Co, C and Koves, TR and Smith, JE and Dworkin, SI},
      title = {Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1997},
      volume = {133},
      number = {1},
      pages = {7-16}
    }
    
    HENRY, D. & WHITE, F. REPEATED COCAINE ADMINISTRATION CAUSES PERSISTENT ENHANCEMENT OF D1 DOPAMINE RECEPTOR SENSITIVITY WITHIN THE RAT NUCLEUS-ACCUMBENS {1991} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {258}({3}), pp. {882-890} 
    article  
    Abstract: The rewarding effects of cocaine are mediated primarily by the mesoaccumbens dopamine (DA) system, which projects from A10 DA cell bodies within the ventral tegmental area to the nucleus accumbens (NAc). This pathway is also intricately involved in the locomotor stimulating effect of cocaine and the progressive increases (sensitization) in this behavior observed after repeated administration of cocaine and other psychomotor stimulants. By using single-cell electrophysiological recording and microiontophoretic techniques, we demonstrated previously that repeated cocaine administration (10 mg/kg i.p., twice daily, 14 days) renders impulse-regulating somatodendritic A10 DA autoreceptors subsensitive, thereby increasing impulse flow within the mesoaccumbens DA system. In striking contrast, inhibitory responses of NAc neurons to iontophoretic DA were significantly increased in cocaine-treated rats tested 16 to 24 hr after the last cocaine injection. In the present study, iontophoretic application of selective D1 (SKF 383393) and D2 (quinpirole) DA receptor agonists was utilized to determine the extent to which each of these DA receptor subtypes is altered by repeated cocaine administration. After 2 weeks of twice daily cocaine (10 mg/kg i.p.) injections, significant increases in the inhibitory responses of NAc neurons to SKF 38393, but not quinpirole, were observed. In addition, this D1 receptor sensitization was still evident when animals were tested either 7 days or 1 month after the final cocaine injection. After 2 months of withdrawal from cocaine treatment, D1 receptor sensitivity in the NAc had returned to control levels. It is proposed that this relatively persistent change in D1 DA receptor sensitivity within the NAc may participate in the development of behavioral sensitization to repeated administration of psychomotor stimulants and may depend upon overactivity of DA neurons within the ventral tegmental area.
    BibTeX:
    @article{HENRY1991,
      author = {HENRY, DJ and WHITE, FJ},
      title = {REPEATED COCAINE ADMINISTRATION CAUSES PERSISTENT ENHANCEMENT OF D1 DOPAMINE RECEPTOR SENSITIVITY WITHIN THE RAT NUCLEUS-ACCUMBENS},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1991},
      volume = {258},
      number = {3},
      pages = {882-890}
    }
    
    HERKENHAM, M., EDLEY, S. & STUART, J. CELL CLUSTERS IN THE NUCLEUS ACCUMBENS OF THE RAT, AND THE MOSAIC RELATIONSHIP OF OPIATE RECEPTORS, ACETYLCHOLINESTERASE AND SUBCORTICAL AFFERENT TERMINATIONS {1984} NEUROSCIENCE
    Vol. {11}({3}), pp. {561-593} 
    article  
    BibTeX:
    @article{HERKENHAM1984,
      author = {HERKENHAM, M and EDLEY, SM and STUART, J},
      title = {CELL CLUSTERS IN THE NUCLEUS ACCUMBENS OF THE RAT, AND THE MOSAIC RELATIONSHIP OF OPIATE RECEPTORS, ACETYLCHOLINESTERASE AND SUBCORTICAL AFFERENT TERMINATIONS},
      journal = {NEUROSCIENCE},
      year = {1984},
      volume = {11},
      number = {3},
      pages = {561-593}
    }
    
    HERKENHAM, M., LYNN, A., DECOSTA, B. & RICHFIELD, E. NEURONAL LOCALIZATION OF CANNABINOID RECEPTORS IN THE BASAL GANGLIA OF THE RAT {1991} BRAIN RESEARCH
    Vol. {547}({2}), pp. {267-274} 
    article  
    Abstract: Cannabinoid receptors have recently been characterized and localized using a high-affinity radiolabeled cannabinoid analog in section binding assays. Is rat brain, the highest receptor densities are in the globus pallidus and substantia nigra pars reticulata. Receptors are also dense in the caudate-putamen. In order to determine the neuronal localization of these receptors, selective lesions of key striatal afferent and efferent systems were made. Striatal neurons and efferent projections were selectively destroyed by unilateral infusion of ibotenic acid into the caudate-putamen. The nigrostriatal pathway was selectively destroyed in another set of animals by infusion of 6-hydroxydopamine into the medial forebrain bundle. After 2- or 4-week survivals, slide-mounted brain sections were incubated with ligands selective for cannabinoid ([H-3]CP 55,940), dopamine D1 ([H-3]SCH-23390) and D2 ([H-3]raclopride) receptors, and dopamine uptake sites ([H-3]GBR-12935). Slides were exposed to H-3-sensitive film. The resulting autoradiography showed ibotenate-induced losses of cannabinoid, D1 and D2 receptors in the caudate-putamen and topographic losses of cannabinoid and D1 receptors in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata at both survivals. Four weeks after medial forebrain bundle lesions (which resulted in amphetamine-induced rotations), there was loss of dopamine uptake sites in the striatum and substantia nigra pars compacta but no change in cannabinoid receptor binding. The data show that cannabinoid receptors in the basal ganglia are neuronally located on striatal projection neurons, including their axons and terminals. Cannabinoid receptors may be co-localized with D1 receptors on striatonigral neurons. Cannabinoid receptors are not localized on dopaminergic nigrostriatal cell bodies or terminals.
    BibTeX:
    @article{HERKENHAM1991,
      author = {HERKENHAM, M and LYNN, AB and DECOSTA, BR and RICHFIELD, EK},
      title = {NEURONAL LOCALIZATION OF CANNABINOID RECEPTORS IN THE BASAL GANGLIA OF THE RAT},
      journal = {BRAIN RESEARCH},
      year = {1991},
      volume = {547},
      number = {2},
      pages = {267-274}
    }
    
    HERNANDEZ, L. & HOEBEL, B. FOOD REWARD AND COCAINE INCREASE EXTRACELLULAR DOPAMINE IN THE NUCLEUS ACCUMBENS AS MEASURED BY MICRODIALYSIS {1988} LIFE SCIENCES
    Vol. {42}({18}), pp. {1705-1712} 
    article  
    BibTeX:
    @article{HERNANDEZ1988,
      author = {HERNANDEZ, L and HOEBEL, BG},
      title = {FOOD REWARD AND COCAINE INCREASE EXTRACELLULAR DOPAMINE IN THE NUCLEUS ACCUMBENS AS MEASURED BY MICRODIALYSIS},
      journal = {LIFE SCIENCES},
      year = {1988},
      volume = {42},
      number = {18},
      pages = {1705-1712}
    }
    
    Herz, A. Endogenous opioid systems and alcohol addiction {1997} PSYCHOPHARMACOLOGY
    Vol. {129}({2}), pp. {99-111} 
    article  
    Abstract: Alcohol exerts numerous pharmacological effects through its interaction with various neurotransmitters and neuromodulators. Among the latter, the endogenous opioids play a key role in the rewarding (addictive) properties of ethanol. Three types of opioid receptors (mu, delta and kappa) represent the respective targets of the major opioid peptides (beta-endorphin, enkephalins and dynorphins, respectively). The rewarding (reinforcing) properties of mu- and delta-receptor ligands are brought about by activation of the mesolimbic dopamine system which ascends from the ventral tegmentum of the midbrain (VTA) to rostral structures; of these, the nucleus accumbens (NAG) is of particular importance in drug addiction. In contrast, dysphoria results from activation of kappa-receptors. The neurochemical manifestations of these opposing effects are, respectively, increases and decreases in dopamine release in the NAG. Several lines of evidence indicate that alcohol interferes with endogenous opioid mechanisms which are closely linked with dopamine transmission in the mesolimbic pathway. The view that condensation products of dopamine and alcohol-derived aldehyde (tetrahydroisoquinolines) play a role remains controversial. There is, however, much information on the direct (acute and chronic) effects of alcohol on the binding properties of opioid receptors, as well as modulation of opioid peptide synthesis and secretion (e.g. a suggested increase in beta-endorphin release). In view of the reinforcing properties of alcohol, it is relevant to consider behavioural studies involving alcohol self-administration in rodents and primates. Low doses of morphine have been found to increase, and higher doses of the opiate to decrease, alcohol consumption. Conversely, opioid antagonists such as naloxone and naltrexone (which bind to non-selectively opioid receptors) have been shown to decrease alcohol consumption under various experimental conditions. Similar results have been reported when selective mu- or delta-receptor antagonists are administered. Results obtained in genetic models of high preference for alcohol also support the view that alcohol intake depends on the activity of the endogenous opioid reward system and that alcohol consumption may serve to compensate for inherent deficits in this system. One hypothetical model proposes that reward results from activation of mu-opioid receptors in the VTA and/or delta-receptors in the NAC; both these nuclei are targets of endogenous beta-endorphin. It is suggested that alcohol interferes with this reward pathway either directly or indirectly. The available experimental data accord well with those obtained from clinical studies in which opioid antagonists have been used to prevent relapse in alcoholics. Conceptual considerations concerning communalities between various forms of addictions are also discussed in this review.
    BibTeX:
    @article{Herz1997,
      author = {Herz, A},
      title = {Endogenous opioid systems and alcohol addiction},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1997},
      volume = {129},
      number = {2},
      pages = {99-111}
    }
    
    HIROTA, S., ITO, A., MORII, E., WANAKA, A., TOHYAMA, M., KITAMURA, Y. & NOMURA, S. LOCALIZATION OF MESSENGER-RNA FOR C-KIT RECEPTOR AND ITS LIGAND IN THE BRAIN OF ADULT-RATS - AN ANALYSIS USING INSITU HYBRIDIZATION HISTOCHEMISTRY {1992} MOLECULAR BRAIN RESEARCH
    Vol. {15}({1-2}), pp. {47-54} 
    article  
    Abstract: Localization of mRNA for the c-kit receptor and its ligand (Sl factor) in the brain of adult rats was studied using in situ hybridization histochemistry. The mRNA for the c-kit receptor was detected in the forebrain, the lower brain stem and the cerebellum. In the forebrain, the c-kit mRNA signals were detected in the olfactory bulb, the caudate-putamen, throughout the superficial cortex, the accumbens nucleus, the nucleus of vertical limb diagonal band, the bed nucleus of anterior commissure, Ammon's horn, the entopeduncular nucleus, the subthalamic nucleus, the dorsal raphe nucleus, the parasubiculum, the presubiculum, the ventricular nucleus of lateral lemniscus. and the entorhinal cortex. In the lower brain stem, the signals were detected in the inferior colliculus, the spinal vestibular nucleus. the spinal tract nucleus of trigeminal nerve, and the pyramidal tract. In the cerebellum, the signals were detected in the molecular layer of the cortex and cerebellar nuclei. By contrast, the signals of mRNA for Sl factor were detected in the forebrain and the cerebellum. In the forebrain, the signals were detected in the olfactory bulb, the endopiriform nucleus. the septohippocampal nucleus, the habenular nuclei, and most of the thalamic nuclei. In the cerebellum, the signals were detected in Purkinje cells. Several pairs of structures were found in which mRNA of either the c-kit receptor or the Sl factor was expressed and between which the synaptic connection had been reported, suggesting that the interaction between the c-kit receptor and the Sl factor may play some roles in the development of such synaptic connections.
    BibTeX:
    @article{HIROTA1992,
      author = {HIROTA, S and ITO, A and MORII, E and WANAKA, A and TOHYAMA, M and KITAMURA, Y and NOMURA, S},
      title = {LOCALIZATION OF MESSENGER-RNA FOR C-KIT RECEPTOR AND ITS LIGAND IN THE BRAIN OF ADULT-RATS - AN ANALYSIS USING INSITU HYBRIDIZATION HISTOCHEMISTRY},
      journal = {MOLECULAR BRAIN RESEARCH},
      year = {1992},
      volume = {15},
      number = {1-2},
      pages = {47-54}
    }
    
    HOOKS, M., JONES, G., SMITH, A., NEILL, D. & JUSTICE, J. RESPONSE TO NOVELTY PREDICTS THE LOCOMOTOR AND NUCLEUS-ACCUMBENS DOPAMINE RESPONSE TO COCAINE {1991} SYNAPSE
    Vol. {9}({2}), pp. {121-128} 
    article  
    Abstract: The relationship between a rat's locomotor response to a novel environment and its behavioral and dopaminergic responses to cocaine was examined. Subjects were divided into two groups based on their locomotor response to a novel environment. Subjects who had a novelty response above the median were classified as high responders (HR), while those with a novelty response below the median were classified as low responders (LR). Following administration of cocaine-HCl (0, 2.5, 5.0, 10.0, or 15.0 mg/kg), HR rats showed a greater locomotor response than LR rats. Moreover, there was a significant correlation between a subject's locomotor response to the novel environment and the locomotor response to either 10.0 (r = 0.65) or 15.0 (r = 0.92) mg/kg cocaine. In a separate experiment, the extracellular concentration of dopamine in the nucleus accumbens (NACC) was monitored using microdialysis procedures. Following cocaine administration (15.0 mg/kg) HR rats showed a larger NACC dopamine response and greater locomotor activity than LR rats. In addition, there was a threefold greater locomotor activity to dopamine ratio in HR rats than in LR rats. A correlation between a subject's locomotor response to a novel environment and the dopaminergic response to cocaine was also evident. These results suggest that differences in the locomotor response to cocaine can, to some degree, be predicted by a rat's locomotor response to a novel environment, and that variations in dopamine-dependent mechanisms of the NACC may underlie these individual differences.
    BibTeX:
    @article{HOOKS1991,
      author = {HOOKS, MS and JONES, GH and SMITH, AD and NEILL, DB and JUSTICE, JB},
      title = {RESPONSE TO NOVELTY PREDICTS THE LOCOMOTOR AND NUCLEUS-ACCUMBENS DOPAMINE RESPONSE TO COCAINE},
      journal = {SYNAPSE},
      year = {1991},
      volume = {9},
      number = {2},
      pages = {121-128}
    }
    
    HOPE, B., KOSOFSKY, B., HYMAN, S. & NESTLER, E. REGULATION OF IMMEDIATE EARLY GENE-EXPRESSION AND AP-1 BINDING IN THE RAT NUCLEUS-ACCUMBENS BY CHRONIC COCAINE {1992} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {89}({13}), pp. {5764-5768} 
    article  
    Abstract: Chronic treatment of rats with cocaine leads to long-term biochemical changes in the nucleus accumbens (NAc), a brain region implicated in mediating the reinforcing effects of cocaine and other drugs of abuse. Immediate early genes (IEGs) and their protein products appear to play an important role in transducing extracellular stimuli into altered patterns of cellular gene expression and, therefore, into long-term changes in cellular functioning. We therefore examined changes in the mRNA levels for the IEGs c-fos, c-jun, fosB, junB, and zif268 in the NAc of rats treated acutely and chronically with cocaine. A single cocaine injection increased the mRNA levels of all of the IEGs examined. Following chronic cocaine treatment, however, IEG expression had returned to control levels and was not significantly increased following a further acute challenge with cocaine, suggesting desensitization in the ability of cocaine to induce these IEGs. Similarly, levels of Fos-like immunoreactivity, which are increased in the NAc by acute cocaine, were reduced to control levels in chronic cocaine-treated rats. Fos, Jun, and a number of related proteins activate or repress transcription of genes by binding to DNA response elements called AP-1 sites. As would be expected from the RNA data and immunohistochemistry, acute cocaine administration increased AP-1 binding activity in the NAc, an effect that reverted completely to control levels within 8-12 hr. In contrast, AP-1 binding activity in the NAc of animals treated chronically with cocaine remained elevated at acute levels 18 hr after the last chronic injection, a time at which c-fos and c-jun mRNA levels and Fos-like immunoreactivity had returned to control values. An additional acute cocaine challenge did not further increase AP-1 binding. The data suggest that chronic cocaine treatment leads to a persistent increase in AP-1 binding activity, which may be involved in some of the physiological and behavioral aspects of cocaine addiction.
    BibTeX:
    @article{HOPE1992,
      author = {HOPE, B and KOSOFSKY, B and HYMAN, SE and NESTLER, EJ},
      title = {REGULATION OF IMMEDIATE EARLY GENE-EXPRESSION AND AP-1 BINDING IN THE RAT NUCLEUS-ACCUMBENS BY CHRONIC COCAINE},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1992},
      volume = {89},
      number = {13},
      pages = {5764-5768}
    }
    
    HOPE, B., NYE, H., KELZ, M., SELF, D., IADAROLA, M., NAKABEPPU, Y., DUMAN, R. & NESTLER, E. INDUCTION OF A LONG-LASTING AP-1 COMPLEX COMPOSED OF ALTERED FOS-LIKE PROTEINS IN BRAIN BY CHRONIC COCAINE AND OTHER CHRONIC TREATMENTS {1994} NEURON
    Vol. {13}({5}), pp. {1235-1244} 
    article  
    Abstract: Following chronic cocaine treatment, we have found a long lasting increase in AP-1 binding in the rat nucleus accumbens and striatum, two important targets of the behavioral effects of cocaine. This increase develops gradually over several days and remains at 50% of maximal levels 7 days after the last cocaine exposure. Supershift experiments, along with one and two-dimensional Western blots, indicate that this chronic AP-1 complex contains at least four Fos-related antigens (FRAs), some of which display Delta FosB-like immunoreactivity, that are induced selectively by chronic, but not acute, cocaine treatment. The same chronic FRAs were also induced by several different types of chronic treatments in a region-specific manner in the brain. Thus, the chronic FRAs and associated chronic AP-1 complex could mediate some of the long-term changes in gene expression unique to the chronic-treated state as opposed to the acute-treated and normal states.
    BibTeX:
    @article{HOPE1994,
      author = {HOPE, BT and NYE, HE and KELZ, MB and SELF, DW and IADAROLA, MJ and NAKABEPPU, Y and DUMAN, RS and NESTLER, EJ},
      title = {INDUCTION OF A LONG-LASTING AP-1 COMPLEX COMPOSED OF ALTERED FOS-LIKE PROTEINS IN BRAIN BY CHRONIC COCAINE AND OTHER CHRONIC TREATMENTS},
      journal = {NEURON},
      year = {1994},
      volume = {13},
      number = {5},
      pages = {1235-1244}
    }
    
    HORGER, B., GILES, M. & SCHENK, S. PREEXPOSURE TO AMPHETAMINE AND NICOTINE PREDISPOSES RATS TO SELF-ADMINISTER A LOW-DOSE OF COCAINE {1992} PSYCHOPHARMACOLOGY
    Vol. {107}({2-3}), pp. {271-276} 
    article  
    Abstract: The acquisition of low-dose (0.25 mg/kg/infusion) intravenous cocaine self-administration was measured in rats that had received nine daily injections of amphetamine (1.0 mg/kg, IP), nicotine (0.6 mg/kg base weight, SC) or vehicle. For control rats, the acquisition of self-administration was gradual with the number of responses per 2 h daily test session increasing between days 3 and 9. By comparison, rats preexposed with amphetamine and nicotine demonstrated elevated response means during the early days of testing, suggesting more rapid acquisition. All groups eventually reached similar asymptotic levels of responding. The enhanced responding observed during the early days of testing in the rats preexposed with amphetamine and nicotine was due to an increased number of subjects that reliably self-administered cocaine. Thus, the rats preexposed with amphetamine and nicotine seemed predisposed to the reinforcing effects of cocaine. In contrast to the self-administration data, preexposure to nicotine failed to sensitize rats to the locomotor activating effects of cocaine. In fact, the same preexposure regimen appeared to produce tolerance to this effect of cocaine. These data give evidence that different mechanisms may mediate sensitization to the reinforcing and locomotor activating effects of cocaine.
    BibTeX:
    @article{HORGER1992,
      author = {HORGER, BA and GILES, MK and SCHENK, S},
      title = {PREEXPOSURE TO AMPHETAMINE AND NICOTINE PREDISPOSES RATS TO SELF-ADMINISTER A LOW-DOSE OF COCAINE},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1992},
      volume = {107},
      number = {2-3},
      pages = {271-276}
    }
    
    Horger, B., Iyasere, C., Berhow, M., Messer, C., Nestler, E. & Taylor, J. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor {1999} JOURNAL OF NEUROSCIENCE
    Vol. {19}({10}), pp. {4110-4122} 
    article  
    Abstract: The mesolimbic dopamine (DA) system has been implicated in drug reward, locomotor sensitization, and responding for reward-related stimuli [termed conditioned reinforcers (CR)]. Here, we investigated the effect of brain-derived neurotrophic factor (BDNF), which enhances the survival and function of dopaminergic neurons, on stimulant-induced locomotor sensitization and responding for CR. In experiment 1, BDNF was infused into the nucleus accumbens (NAc) or ventral tegmental area over 2 weeks via chronically implanted minipumps (1-2.5 mu g/d), and the psychomotor stimulant effects of cocaine (5-15 mg/kg, i.p.) were studied. We found that BDNF enhanced the initial stimulant effects of cocaine and seemed to facilitate the development of sensitization to repeated cocaine doses. In experiment 2, we studied the effects of intra-NAc BDNF infusions on responding for CR. BDNF-treated rats showed twice as many CR responses compared with controls when saline was first administered. BDNF enhanced responding on the CR lever more than four times that seen in control animals after a cocaine injection (10 mg/kg, i.p.). The enhanced response to cocaine in BDNF-treated animals persisted for more than a month after the BDNF infusions had stopped, indicating longlasting changes in the mesolimbic DA system caused by BDNF administration. In experiment 3, we examined locomotor sensitization to cocaine in heterozygous BDNF knock-out mice and found that the development of sensitization was delayed compared with wild-type littermates. These results demonstrate the profound effects of BDNF on the enhancement of both cocaine-induced locomotion and facilitation of CR and suggest a possible role for BDNF in long-term adaptations of the brain to cocaine.
    BibTeX:
    @article{Horger1999,
      author = {Horger, BA and Iyasere, CA and Berhow, MT and Messer, CJ and Nestler, EJ and Taylor, JR},
      title = {Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1999},
      volume = {19},
      number = {10},
      pages = {4110-4122}
    }
    
    Hui, K., Liu, J., Makris, N., Gollub, R., Chen, A., Moore, C., Kennedy, D., Rosen, B. & Kwong, K. Acupuncture modulates the limbic system and subcortical gray structures of the human brain: Evidence from fMRI studies in normal subjects {2000} HUMAN BRAIN MAPPING
    Vol. {9}({1}), pp. {13-25} 
    article  
    Abstract: Acupuncture, an ancient therapeutic technique, is emerging as an important modality of complementary medicine in the United States. The use and efficacy of acupuncture treatment are not yet widely accepted in Western scientific and medical communities. Demonstration of regionally specific, quantifiable acupuncture effects on relevant structures of the human brain would facilitate acceptance and integration of this therapeutic modality into the practice of modem medicine. Research with animal models of acupuncture indicates that many of the beneficial effects may be mediated at the subcortical level in the brain. We used functional magnetic resonance imaging (fMRI) to investigate the effects of acupuncture in normal subjects and to provide a foundation for future studies on mechanisms of acupuncture action in therapeutic interventions. Acupuncture needle manipulation was performed at Large Intestine 4 (LI 4, Hegu) on the hand in 13 subjects [Stux, 1997]. Needle manipulation on either hand produced prominent decreases of fMRI signals in the nucleus accumbens, amygdala, hippocampus, parahippocampus, hypothalamus, ventral tegmental area, anterior cingulate gyrus (BA 24), caudate, putamen, temporal pole, and insula in all 11 subjects who experienced acupuncture sensation. In marked contrast, signal increases were observed primarily in the somatosensory cortex. The two subjects who experienced pain instead of acupuncture sensation exhibited signal increases instead of decreases in the anterior cingulate gyrus (BA 24), caudate, putamen, anterior thalamus, and posterior insula. Superficial tactile stimulation to the same area elicited signal increases in the somatosensory cortex as expected, but no signal decreases in the deep structures. These preliminary results suggest that acupuncture needle manipulation modulates the activity of the limbic system and subcortical structures. We hypothesize that modulation of subcortical structures may be an important mechanism by which acupuncture exerts its complex multisystem effects. (C) 2000 Wiley-Liss, Inc.
    BibTeX:
    @article{Hui2000,
      author = {Hui, KKS and Liu, J and Makris, N and Gollub, RL and Chen, AJW and Moore, CI and Kennedy, DN and Rosen, BR and Kwong, KK},
      title = {Acupuncture modulates the limbic system and subcortical gray structures of the human brain: Evidence from fMRI studies in normal subjects},
      journal = {HUMAN BRAIN MAPPING},
      year = {2000},
      volume = {9},
      number = {1},
      pages = {13-25}
    }
    
    HURD, Y. & HERKENHAM, M. MOLECULAR ALTERATIONS IN THE NEOSTRIATUM OF HUMAN COCAINE ADDICTS {1993} SYNAPSE
    Vol. {13}({4}), pp. {357-369} 
    article  
    Abstract: Molecular changes in the neostriatum of human subjects who died with a history of cocaine abuse were revealed in discrete cell populations by means of the techniques of in situ hybridization histochemistry and in vitro receptor binding and autoradiography. Cocaine subjects had a history of repeated cocaine use and had cocaine and/or cocaine metabolites on board at the time of death. These subjects were compared to control subjects that had both a negative history and toxicology of cocaine use. Selective alterations in mRNA levels of striatal neuropeptides were detected in cocaine subjects compared to control subjects, especially for the opioid peptides. Marked reductions in the levels of enkephalin mRNA and mu opiate receptor binding were found in the caudate and putamen, concomitant with elevations in levels of dynorphin mRNA and kappa opiate receptor binding in the putamen and caudate, respectively. Dopamine uptake site binding was reduced in the caudate and putamen of cocaine subjects. The greater magnitude of changes in the dorsolateral striatum (caudate and putamen) as opposed to the ventromedial striatum (nucleus accumbens) suggests that cocaine abuse preferentially alters the biosynthetic activity of striatal systems associated with sensorimotor functioning. Additionally, an imbalance in the activity of the two major striatal output pathways in cocaine users is implicated because peptide mRNA levels were reduced in enkephalinergic striatopallidal neurons and increased in dynorphinergic striatonigral neurons. Another imbalance, that of reductions of transmitter mRNA and receptor expression associated with euphoria (enkephalin and mu opiate receptors), together with elevations in mRNAs of transmitter systems associated with dysphoria (dynorphin and kappa opiate receptors), suggests a model of dysphoria and craving in the human cocaine addict brain.
    BibTeX:
    @article{HURD1993,
      author = {HURD, YL and HERKENHAM, M},
      title = {MOLECULAR ALTERATIONS IN THE NEOSTRIATUM OF HUMAN COCAINE ADDICTS},
      journal = {SYNAPSE},
      year = {1993},
      volume = {13},
      number = {4},
      pages = {357-369}
    }
    
    HURLEY, K., HERBERT, H., MOGA, M. & SAPER, C. EFFERENT PROJECTIONS OF THE INFRALIMBIC CORTEX OF THE RAT {1991} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {308}({2}), pp. {249-276} 
    article  
    Abstract: On the basis of stimulation studies, it has been proposed that the infralimbic cortex (ILC), Brodmann area 25, may serve as an autonomic motor cortex. To explore this hypothesis, we have combined anterograde tracing with Phaseolus vulgaris leucoagglutinin (PHA-L) and retrograde tracing with wheat germ aggutinin conjugated to horseradish peroxidase (WGA-HRP) to determine the efferent projections from the ILC. Axons exit the ILC in one of three efferent pathways. The dorsal pathway ascends through layers III and V to innervate the prelimbic and anterior cingulate cortices. The lateral pathway courses through the nucleus accumbens to innervate the insular cortex, the perirhinal cortex, and parts of the piriform cortex. In addition, some fibers from the lateral pathway enter the corticospinal tract. The ventral pathway is by far the largest and innervates the thalamus (including the paraventricular nucleus of the thalamus, the border zone between the paraventricular and medial dorsal nuclei, and the paratenial, reuniens, ventromedial, parafasicular, and subparafasicular nuclei), the hypothalamus (including the lateral hypothalamic and medial preoptic areas, and the suprachiasmatic, dorsomedial, and supramammillary nuclei), the amygdala (including the central, medial, and basomedial nuclei, and the periamygdaloid cortex) and the bed nucleus of the stria terminalis. The ventral efferent pathway also provides descending projections to autonomic cell groups of the brainstem and spinal cord including the periaqueductal gray matter, the parabrachial nucleus, the nucleus of the solitary tract, the dorsal motor vagal nucleus, the nucleus ambiguus, and the ventrolateral medulla, as well as lamina I and the intermediolateral column of the spinal cord. The ILC has extensive projections to central autonomic nuclei that may subserve a role in modulating visceral responses to emotional stimuli, such as stress.
    BibTeX:
    @article{HURLEY1991,
      author = {HURLEY, KM and HERBERT, H and MOGA, MM and SAPER, CB},
      title = {EFFERENT PROJECTIONS OF THE INFRALIMBIC CORTEX OF THE RAT},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1991},
      volume = {308},
      number = {2},
      pages = {249-276}
    }
    
    Hyman, S. & Malenka, R. Addiction and the brain: The neurobiology of compulsion and its persistence {2001} NATURE REVIEWS NEUROSCIENCE
    Vol. {2}({10}), pp. {695-703} 
    article  
    Abstract: People take addictive drugs to elevate mood, but with repeated use these drugs produce serious unwanted effects, which can Include tolerance to some drug effects, sensitization to others, and an adapted state - dependence - which sets the stage for withdrawal symptoms when drug use stops. The most serious consequence of repetitive drug taking, however, is addiction: a persistent state in which compulsive drug use escapes control, even when serious negative consequences ensue, Addiction is characterized by a long-lasting risk of relapse, which is often Initiated by exposure to drug-related cues. Substantial progress has been made in understanding the molecular and cellular mechanisms of tolerance, dependence and withdrawal, but as yet we understand little of the neural substrates of compulsive drug use and its remarkable persistence. Here we review evidence for the possibility that compulsion and its persistence are based on a pathological usurpation of molecular mechanisms that are normally involved in memory.
    BibTeX:
    @article{Hyman2001,
      author = {Hyman, SE and Malenka, RC},
      title = {Addiction and the brain: The neurobiology of compulsion and its persistence},
      journal = {NATURE REVIEWS NEUROSCIENCE},
      year = {2001},
      volume = {2},
      number = {10},
      pages = {695-703}
    }
    
    Hyman, S. & Nestler, E. Initiation and adaptation: A paradigm for understanding psychotropic drug action {1996} AMERICAN JOURNAL OF PSYCHIATRY
    Vol. {153}({2}), pp. {151-162} 
    article  
    Abstract: Objective: This article describes a paradigm-initiation and adaptation-within which to conceptualize the drug-induced neural plasticity that underlies the long-term actions of psychotropic drugs in the brain. Method: Recent advances in neurobiology are reviewed. Results: Recent developments in cellular and molecular neurobiology provide new conceptual and experimental tools for understanding the mechanisms by which psychotropic drugs produce long-lived alterations in brain function. Because of the availability of more robust animal models, the mechanisms by which drugs of abuse produce dependence are better understood than the mechanisms by which antidepressants, antipsychotics, and lithium produce their therapeutic effects. Nonetheless, the fundamental types of mechanisms appear to be similar: chronic drug administration drives the production of adaptations in postreceptor signaling pathways, including regulation of neural gene expression. Whether the results are deleterious or therapeutic depends on the precise neural systems targeted by a particular drug. Conclusions: Biological investigation in psychiatry has often focused too narrowly on synaptic pharmacology, especially on neurotransmitter turnover and neurotransmitter receptors. This review focuses on molecular and cellular changes in neural function that are produced as adaptations to chronic administration of addictive drugs such as psychostimulants and therapeutic drugs such as antidepressants. To understand normal brain function, psychopathology, and the actions of psychiatric treatments, and to exploit the eventual findings of psychiatric genetics, psychiatric research must now extend its efforts beyond the synapse, to an understanding of cellular and molecular neurobiology (in particular, postreceptor signal transduction) as well as to a better understanding of the architecture and function of neural systems. A paradigm is presented to help understand the long-term effects of psychotropic drugs, including the latency in onset of their therapeutic actions.
    BibTeX:
    @article{Hyman1996,
      author = {Hyman, SE and Nestler, EJ},
      title = {Initiation and adaptation: A paradigm for understanding psychotropic drug action},
      journal = {AMERICAN JOURNAL OF PSYCHIATRY},
      year = {1996},
      volume = {153},
      number = {2},
      pages = {151-162}
    }
    
    Ichikawa, J., Ishii, H., Bonaccorso, S., Fowler, W., O'Laughlin, I. & Meltzer, H. 5-HT2A and D-2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release {2001} JOURNAL OF NEUROCHEMISTRY
    Vol. {76}({5}), pp. {1521-1531} 
    article  
    Abstract: Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)(2A) than dopamine D-2 antagonists, may improve negative symptoms and cognitive dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT1A agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT1A receptor activation, as a result of the blockade of 5-HT2A and Dg receptors. M100907 (0.1 mg/ kg), a 5-HT2A antagonist, significantly increased the ability of both S(-)-sulpiride (10 mg/kg), a D-2 antagonist devoid of 5-HT1A affinity, and R(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT1A agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT1A antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT1A partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT2A and Dp receptor blockade, regardless of intrinsic 5-HT1A affinity, may promote the ability of 5-HT1A receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT2A antagonists and typical APDs, which are Dp antagonists, may facilitate 5-HT1A agonist activity.
    BibTeX:
    @article{Ichikawa2001,
      author = {Ichikawa, J and Ishii, H and Bonaccorso, S and Fowler, WL and O'Laughlin, IA and Meltzer, HY},
      title = {5-HT2A and D-2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {2001},
      volume = {76},
      number = {5},
      pages = {1521-1531}
    }
    
    Ikemoto, S. & Panksepp, J. The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking {1999} BRAIN RESEARCH REVIEWS
    Vol. {31}({1}), pp. {6-41} 
    article  
    Abstract: Studies addressing behavioral functions of dopamine (DA) in the nucleus accumbens septi (NAS) are reviewed. A role of NAS DA in reward has long been suggested. However, some investigators have questioned the role of NAS DA in rewarding effects because of its role in aversive contexts. As findings supporting the role of NAS DA in mediating aversively motivated behaviors accumulate, it is necessary to accommodate such data for understanding the role of NAS DA in behavior. The aim of the present paper is to provide a unifying interpretation that can account for the functions of NAS DA in a variety of behavioral contexts: (1) its role in appetitive behavioral arousal, (2) its role as a facilitator as well as an inducer of reward processes, and (3) its presently undefined role in aversive contexts. The present analysis suggests that NAS DA plays an important role in sensorimotor integrations that facilitate flexible approach responses. Flexible approach responses an contrasted with fixed instrumental approach responses (habits), which may involve the nigro-striatal DA system more than the meso-accumbens DA system. Functional properties of NAS DA transmission are considered in two stages: unconditioned behavioral invigoration effects and incentive learning effects. (1) When organisms are presented with salient stimuli (e.g., novel stimuli and incentive stimuli), NAS DA is released and invigorates flexible approach responses (invigoration effects). (2) When proximal exteroceptive receptors are stimulated by unconditioned stimuli, NAS DA is released and enables stimulus representations to acquire incentive properties within specific environmental context. It is important to make a distinction that NAS DA is a critical component for the conditional formation of incentive representations but not the retrieval of incentive stimuli or behavioral expressions based on over-learned incentive responses (i.e., habits). Nor is NAS DA essential for the cognitive perception of environmental stimuli. Therefore, even without normal NAS DA transmission, the habit response system still allows animals to perform instrumental responses given that the tasks take place in fixed environment. Such a role of NAS DA as an incentive-property constructor is not limited to appetitive contexts but also aversive contexts. This dual action of NAS DA in invigoration and incentive learning may explain the rewarding effects of NAS DA as well as other effects of NAS DA in a variety of contexts including avoidance and unconditioned/conditioned increases in open-field locomotor activity. Particularly, the present hypothesis offers the following interpretation for the finding that both conditioned and unconditioned aversive stimuli stimulate DA release in the NAS: NAS DA invigorates approach responses toward `safety'. Moreover. NAS DA modulates incentive properties of the environment so that organisms emit approach responses toward `safety' (i.e., avoidance responses) when animals later encounter similar environmental contexts. There may be no obligatory relationship between NAS DA release and positive subjective effects, even though these systems probably interact with other brain systems which can mediate such effects. The present conceptual framework may be valuable in understanding the dynamic interplay of NAS DA neurochemistry and behavior, both normal and pathophysiological. (C) 1999 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{Ikemoto1999,
      author = {Ikemoto, S and Panksepp, J},
      title = {The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {1999},
      volume = {31},
      number = {1},
      pages = {6-41}
    }
    
    IMPERATO, A., ANGELUCCI, L., CASOLINI, P., ZOCCHI, A. & PUGLISIALLEGRA, S. REPEATED STRESSFUL EXPERIENCES DIFFERENTLY AFFECT LIMBIC DOPAMINE RELEASE DURING AND FOLLOWING STRESS {1992} BRAIN RESEARCH
    Vol. {577}({2}), pp. {194-199} 
    article  
    Abstract: The effects of repeated restraint stress exposures (daily 60 min, for 6 days) on extracellular dopamine in the nucleus accumbens, during and after the stress experience, have been investigated in rats by in vivo microdialysis. On the first day, restraint increased dopamine release during the first 40 min followed by a return to basal levels (50-60 min later). As soon as restraint ceased and the rats were set free, there was another increase in dopamine release lasting 40 min. On the second and third day, restraint produced only a slight increase in dopamine release, while no significant changes were evident from the fourth to the sixth day. By contrast, from the second to the sixth day the increase in dopamine release observed once rats were freed, was unchanged in comparison to the first day. The present results show that the activation of the mesolimbic dopaminergic system induced by aversive stimuli adapts to repeated experiences differently from that produced by pleasurable events, suggesting that aversive and rewarding experiences involve different neural systems.
    BibTeX:
    @article{IMPERATO1992,
      author = {IMPERATO, A and ANGELUCCI, L and CASOLINI, P and ZOCCHI, A and PUGLISIALLEGRA, S},
      title = {REPEATED STRESSFUL EXPERIENCES DIFFERENTLY AFFECT LIMBIC DOPAMINE RELEASE DURING AND FOLLOWING STRESS},
      journal = {BRAIN RESEARCH},
      year = {1992},
      volume = {577},
      number = {2},
      pages = {194-199}
    }
    
    IMPERATO, A. & DICHIARA, G. PREFERENTIAL STIMULATION OF DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS OF FREELY MOVING RATS BY ETHANOL {1986} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {239}({1}), pp. {219-228} 
    article  
    BibTeX:
    @article{IMPERATO1986,
      author = {IMPERATO, A and DICHIARA, G},
      title = {PREFERENTIAL STIMULATION OF DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS OF FREELY MOVING RATS BY ETHANOL},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1986},
      volume = {239},
      number = {1},
      pages = {219-228}
    }
    
    IMPERATO, A., HONORE, T. & JENSEN, L. DOPAMINE RELEASE IN THE NUCLEUS-CAUDATUS AND IN THE NUCLEUS-ACCUMBENS IS UNDER GLUTAMATERGIC CONTROL THROUGH NON-NMDA RECEPTORS - A STUDY IN FREELY-MOVING RATS {1990} BRAIN RESEARCH
    Vol. {530}({2}), pp. {223-228} 
    article  
    BibTeX:
    @article{IMPERATO1990a,
      author = {IMPERATO, A and HONORE, T and JENSEN, LH},
      title = {DOPAMINE RELEASE IN THE NUCLEUS-CAUDATUS AND IN THE NUCLEUS-ACCUMBENS IS UNDER GLUTAMATERGIC CONTROL THROUGH NON-NMDA RECEPTORS - A STUDY IN FREELY-MOVING RATS},
      journal = {BRAIN RESEARCH},
      year = {1990},
      volume = {530},
      number = {2},
      pages = {223-228}
    }
    
    IMPERATO, A., PUGLISIALLEGRA, S., CASOLINI, P. & ANGELUCCI, L. CHANGES IN BRAIN DOPAMINE AND ACETYLCHOLINE-RELEASE DURING AND FOLLOWING STRESS ARE INDEPENDENT OF THE PITUITARY-ADRENOCORTICAL AXIS {1991} BRAIN RESEARCH
    Vol. {538}({1}), pp. {111-117} 
    article  
    Abstract: Microdialysis was employed to assess extracellular dopamine from medial prefrontal cortex, nucleus accumbens, nucleus caudatus, and acetylcholine from the hippocampus of conscious rats during and after 120 min restraint stress. Restraint stress rapidly stimulated the release and the metabolism of dopamine in the medial prefrontal cortex and in the nucleus accumbens, and acetylcholine release in the hippocampus. Fifty-sixty min later, although rats were still restrained, dopamine and acetylcholine release gradually returned to basal levels. When the animals were freed a considerable increase in the release of both neurotransmitters was observed. No changes in the striatum were observed throughout the experiments. The time-course of plasma corticosterone did not parallel that of dopamine and acetylcholine release, increasing during the whole stress procedure, and decreasing when the animals were released. Adrenalectomized rats responded to stress and liberation in much the same way as intact rats. The administration of exogenous corticosterone (0.5-1.5 mg/kg s.c.) did not change the release of dopamine from the prefrontal cortex and nucleus accumbens, and of acetylcholine from the hippocampus, while the dose of 3.0 mg/kg which stimulated them, raised plasma corticosterone to very high concentrations which had never been attained during stress. Moreover, RU 38486, an antagonist of brain glucocorticoid receptors, did not antagonize the stress-induced increase of neurotransmitter release. These results demonstrate that: (1) dopamine release in the medial prefrontal cortex and nucleus accumbens, and acetylcholine release in the hippocampus are stimulated by restraint stress as well as by freeing the animal, suggesting that such activation may be a neurochemical correlate of emotional arousal produced by sudden environmental changes; (2) there is no cause-effect relationship between increase in plasma corticosterone and increase in dopamine and acetylcholine release.
    BibTeX:
    @article{IMPERATO1991,
      author = {IMPERATO, A and PUGLISIALLEGRA, S and CASOLINI, P and ANGELUCCI, L},
      title = {CHANGES IN BRAIN DOPAMINE AND ACETYLCHOLINE-RELEASE DURING AND FOLLOWING STRESS ARE INDEPENDENT OF THE PITUITARY-ADRENOCORTICAL AXIS},
      journal = {BRAIN RESEARCH},
      year = {1991},
      volume = {538},
      number = {1},
      pages = {111-117}
    }
    
    IMPERATO, A., SCROCCO, M., BACCHI, S. & ANGELUCCI, L. NMDA RECEPTORS AND INVIVO DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS AND NUCLEUS-CAUDATUS {1990} EUROPEAN JOURNAL OF PHARMACOLOGY
    Vol. {187}({3}), pp. {555-556} 
    article  
    BibTeX:
    @article{IMPERATO1990,
      author = {IMPERATO, A and SCROCCO, MG and BACCHI, S and ANGELUCCI, L},
      title = {NMDA RECEPTORS AND INVIVO DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS AND NUCLEUS-CAUDATUS},
      journal = {EUROPEAN JOURNAL OF PHARMACOLOGY},
      year = {1990},
      volume = {187},
      number = {3},
      pages = {555-556}
    }
    
    INSEL, T. & SHAPIRO, L. OXYTOCIN RECEPTOR DISTRIBUTION REFLECTS SOCIAL-ORGANIZATION IN MONOGAMOUS AND POLYGAMOUS VOLES {1992} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {89}({13}), pp. {5981-5985} 
    article  
    Abstract: The neuropeptide oxytocin has been implicated in the mediation of several forms of affiliative behavior including parental care, grooming, and sex behavior. Here we demonstrate that species from the genus Microtus (voles) selected for differences in social affiliation show contrasting patterns of oxytocin receptor expression in brain. By in vitro receptor autoradiography with an iodinated oxytocin analogue, specific binding to brain oxytocin receptors was observed in both the monogamous prairie vole (Microtus ochrogaster) and the polygamous montane vole (Microtus montanus). In the prairie vole, oxytocin receptor density was highest in the prelimbic cortex, bed nucleus of the stria terminalis, nucleus accumbens, midline nuclei of the thalamus, and the lateral aspects of the amygdala. These brain areas showed little binding in the montane vole, in which oxytocin receptors were localized to the lateral septum, ventromedial nucleus of the hypothalamus, and cortical nucleus of the amygdala. Similar differences in brain oxytocin receptor distribution were observed in two additional species, the monogamous pine vole (Microtus pinetorum) and the polygamous meadow vole (Microtus pennsylvanicus). Receptor distributions for two other neurotransmitter systems implicated in the mediation of social behavior, benzodiazepines, and mu-opioids did not show comparable species differences. Furthermore, in the montane vole, which shows little affiliative behavior except during the postpartum period, brain oxytocin receptor distribution changed within 24 hr of parturition, concurrent with the onset of maternal behavior. We suggest that variable expression of the oxytocin receptor in brain may be an important mechanism in evolution of species-typical differences in social bonding and affiliative behavior.
    BibTeX:
    @article{INSEL1992,
      author = {INSEL, TR and SHAPIRO, LE},
      title = {OXYTOCIN RECEPTOR DISTRIBUTION REFLECTS SOCIAL-ORGANIZATION IN MONOGAMOUS AND POLYGAMOUS VOLES},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1992},
      volume = {89},
      number = {13},
      pages = {5981-5985}
    }
    
    Ito, R., Dalley, J., Howes, S., Robbins, T. & Everitt, B. Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats {2000} JOURNAL OF NEUROSCIENCE
    Vol. {20}({19}), pp. {7489-7495} 
    article  
    Abstract: The dopaminergic innervation of the nucleus accumbens is generally agreed to mediate the primary reinforcing and locomotor effects of psychostimulants, but there is less consensus on conditioned dopamine (DA) release during drug-seeking behavior. We investigated the neurochemical correlates of drug-seeking behavior under the control of a drug-associated cue [a light conditioned stimulus (CS+)] and to noncontingent presentations of the CS+ in the core and shell subregions of the nucleus accumbens. Rats self-administered cocaine under a continuous reinforcement schedule in which a response on one of two identical levers led to an intravenous cocaine infusion (0.25 mg/infusion) and a 20 sec light CS+. Response requirements for cocaine and the CS+ were then progressively increased until stable responding was established under a second-order schedule of reinforcement. During microdialysis, rats were presented noncontingently with a set of 10 sec CS+ and neutral tone stimuli (CS-) before and after a 90 min period during which they responded for cocaine under a second-order schedule. Results showed the following: (1) nucleus accumbens DA increased in both the core and shell during intravenous cocaine self-administration; (2) noncontingent presentations of a cocaine-associated CS+ led to increased DA release selectively in the nucleus accumbens core; and (3) extracellular DA levels were unaltered in both core and shell during a protracted period of drug-seeking behavior under the control of the same cocaine-associated cue. These results indicate that the mesolimbic dopamine system is activated after exposure to drug-associated stimuli under specific conditions.
    BibTeX:
    @article{Ito2000,
      author = {Ito, R and Dalley, JW and Howes, SR and Robbins, TW and Everitt, BJ},
      title = {Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2000},
      volume = {20},
      number = {19},
      pages = {7489-7495}
    }
    
    JACKSON, D., ANDEN, N. & DAHLSTROM, A. FUNCTIONAL EFFECT OF DOPAMINE IN NUCLEUS ACCUMBENS AND IN SOME OTHER DOPAMINE-RICH PARTS OF RAT-BRAIN {1975} PSYCHOPHARMACOLOGIA
    Vol. {45}({2}), pp. {139-149} 
    article  
    BibTeX:
    @article{JACKSON1975,
      author = {JACKSON, DM and ANDEN, NE and DAHLSTROM, A},
      title = {FUNCTIONAL EFFECT OF DOPAMINE IN NUCLEUS ACCUMBENS AND IN SOME OTHER DOPAMINE-RICH PARTS OF RAT-BRAIN},
      journal = {PSYCHOPHARMACOLOGIA},
      year = {1975},
      volume = {45},
      number = {2},
      pages = {139-149}
    }
    
    JACKSON, D. & WESTLINDDANIELSSON, A. DOPAMINE-RECEPTORS - MOLECULAR-BIOLOGY, BIOCHEMISTRY AND BEHAVIORAL-ASPECTS {1994} PHARMACOLOGY & THERAPEUTICS
    Vol. {64}({2}), pp. {291-370} 
    article  
    Abstract: The description of new dopamine (DA) receptor subtypes, D1-(D1 and D5) and D2-like (D2A, D2B, D3, D4), has given an impetus to DA research. While selective agonists and antagonists are not generally available yet, the receptor distribution in the brain suggests that they could be new targets for drug development. Binding characteristics and second messenger coupling has been explored in cell lines expressing the new cloned receptors. The absence of selective ligands has meant that in vivo studies have lagged behind. However, progress has been made in understanding the function of DA-containing discrete brain nuclei and the functional consequence of the DA's interaction with other neurotransmitters. This review explores some of the latest advances in these various areas.
    BibTeX:
    @article{JACKSON1994,
      author = {JACKSON, DM and WESTLINDDANIELSSON, A},
      title = {DOPAMINE-RECEPTORS - MOLECULAR-BIOLOGY, BIOCHEMISTRY AND BEHAVIORAL-ASPECTS},
      journal = {PHARMACOLOGY & THERAPEUTICS},
      year = {1994},
      volume = {64},
      number = {2},
      pages = {291-370}
    }
    
    JACOBOWITZ, D. & WINSKY, L. IMMUNOCYTOCHEMICAL LOCALIZATION OF CALRETININ IN THE FOREBRAIN OF THE RAT {1991} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {304}({2}), pp. {198-218} 
    article  
    Abstract: The distribution of the calcium binding protein calretinin (protein 10) was examined in the rat forebrain by immunohistochemistry. The main and accessory olfactory bulbs had immunoreactive label in granule, periglomerular, and mitral cells. Positive fibers were noted in the external plexiform and granule cell layers, glomeruli, and in the molecular layer of the anterior olfactory nucleus. The cerebral cortex contained calretinin label in nonpyramidal bipolar cells. Cells in the substantia nigra compacta and ventral tegmental area were also calretinin positive as were nigrostriatal and mesolimbic projections (caudate-putamen, nucleus accumbens). In the hippocampus, interneurons were stained in all the subfields of the CA1-CA4 regions. In the thalamus, many positive cells were observed in the periventricular, reticular, lateral habenula, and reunions nuclei. Calretinin immunoreactive cells were particularly abundant in the lateral mamillary and septofimbrial nuclei. Several fiber tracts were also revealed, i. e., the lateral olfactory tract, mamillothalamic tract, fasciculus retroflexus, optic tract, and stria medullaris. These results demonstrate a distinct distribution of calretinin within cell bodies and fibers.
    BibTeX:
    @article{JACOBOWITZ1991,
      author = {JACOBOWITZ, DM and WINSKY, L},
      title = {IMMUNOCYTOCHEMICAL LOCALIZATION OF CALRETININ IN THE FOREBRAIN OF THE RAT},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1991},
      volume = {304},
      number = {2},
      pages = {198-218}
    }
    
    JATLOW, P., ELSWORTH, J., BRADBERRY, C., WINGER, G., TAYLOR, J., RUSSELL, R. & ROTH, R. COCAETHYLENE - A NEUROPHARMACOLOGICALLY ACTIVE METABOLITE ASSOCIATED WITH CONCURRENT COCAINE-ETHANOL INGESTION {1991} LIFE SCIENCES
    Vol. {48}({18}), pp. {1787-1794} 
    article  
    Abstract: High concentrations of cocaethylene (EC), the ethyl ester of benzoylecgonine, were measured in the blood of individuals who had concurrently used cocaine and ethanol. Since the powerful reinforcing effects of cocaine appear to be dependent on inhibition of dopamine reuptake in brain, we compared the effects of EC on the dopamine uptake system and its behavioral effects with those of cocaine. EC was equipotent to cocaine with respect to inhibition of binding of [H-3]GBR 12395 to the dopamine reuptake complex, inhibition of [H-3]dopamine uptake into synaptosomes and in its ability to increase extracellular dopamine concentration in the nucleus accumbens following its systemic administration to rats. Moreover, in rats, EC and cocaine each increased locomotor activity and rearing to the same extent following i.p. administration. In self-administration studies in primates, EC was approximately equipotent to cocaine in maintaining responding. The in vivo formation of this active, transesterified ethyl homolog of cocaine may contribute to the effects and consequences of combined cocaine and ethanol abuse.
    BibTeX:
    @article{JATLOW1991,
      author = {JATLOW, P and ELSWORTH, JD and BRADBERRY, CW and WINGER, G and TAYLOR, JR and RUSSELL, R and ROTH, RH},
      title = {COCAETHYLENE - A NEUROPHARMACOLOGICALLY ACTIVE METABOLITE ASSOCIATED WITH CONCURRENT COCAINE-ETHANOL INGESTION},
      journal = {LIFE SCIENCES},
      year = {1991},
      volume = {48},
      number = {18},
      pages = {1787-1794}
    }
    
    Jay, T. Dopamine: a potential substrate for synaptic plasticity and memory mechanisms {2003} PROGRESS IN NEUROBIOLOGY
    Vol. {69}({6}), pp. {375-390} 
    article DOI  
    Abstract: It is only recently that a number of studies on synaptic plasticity in the hippocampus and other brain areas have considered that a heterosynaptic modulatory input could be recruited as well as the coincident firing of pre- and post-synaptic neurons. So far, the strongest evidence for such a regulation has been attributed to dopaminergic (DA) systems but other modulatory pathways have also been considered to influence synaptic plasticity. This review will focus on dopamine contribution to synaptic plasticity in different brain areas (hippocampus, striatum and prefrontal cortex) with, for each region, a few lines on the distribution of DA projections and receptors. New insights into the possible mechanisms underlying these plastic changes will be considered. The contribution of various DA systems in certain forms of learning and memory will be reviewed with recent advances supporting the hypothesis of similar cellular mechanisms underlying DA regulation of synaptic plasticity and memory processes in which the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway has a potential role. To summarize, endogenous DA, which depends on the activity patterns of DA midbrain neurons in freely moving animals. appears as a key regulator in specific synaptic changes observed at certain stages of learning and memory and of synaptic plasticity. (C) 2003 Elsevier Ltd. All rights reserved.
    BibTeX:
    @article{Jay2003,
      author = {Jay, TM},
      title = {Dopamine: a potential substrate for synaptic plasticity and memory mechanisms},
      journal = {PROGRESS IN NEUROBIOLOGY},
      year = {2003},
      volume = {69},
      number = {6},
      pages = {375-390},
      doi = {{10.1016/S0301-0082(03)00085-6}}
    }
    
    Jentsch, J. & Roth, R. The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia {1999} NEUROPSYCHOPHARMACOLOGY
    Vol. {20}({3}), pp. {201-225} 
    article  
    Abstract: Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology,findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia, Moreover, a history of eexperimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered. [Neuropsychopharmacology 20:201-225, 1999] (C) 1999 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.
    BibTeX:
    @article{Jentsch1999,
      author = {Jentsch, JD and Roth, RH},
      title = {The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia},
      journal = {NEUROPSYCHOPHARMACOLOGY},
      year = {1999},
      volume = {20},
      number = {3},
      pages = {201-225}
    }
    
    Jentsch, J. & Taylor, J. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli {1999} PSYCHOPHARMACOLOGY
    Vol. {146}({4}), pp. {373-390} 
    article  
    Abstract: Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such. addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behaviors. These phenomena have been linked with dopamine function within the ventral striatum and amygdala and have been described specifically in terms of motivational and incentive learning processes. New data are emerging that suggest that regions of the frontal cortex involved in inhibitory response control are directly affected by long-term exposure to drugs of abuse. The result of chronic drug use may be frontal cortical cognitive dysfunction, resulting in an inability to inhibit inappropriate unconditioned or conditioned responses elicited by drugs, by related stimuli or by internal drive states. Drug-seeking behavior may thus be due to two related phenomena: (1) augmented incentive motivational qualities of the drug and associated stimuli (due to limbic/amygdalar dysfunction) and (2) impaired inhibitory control (due to frontal cortical dysfunction). In this review, we consider the neuro-anatomical and neurochemical substrates subserving inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking. The evidence for cognitive impulsivity in drug abuse associated with dysfunction of the frontostriatal system will be discussed, and an integrative hypothesis for compulsive reward-seeking in drug abuse will be presented.
    BibTeX:
    @article{Jentsch1999a,
      author = {Jentsch, JD and Taylor, JR},
      title = {Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1999},
      volume = {146},
      number = {4},
      pages = {373-390}
    }
    
    JIANG, Z. & NORTH, R. MEMBRANE-PROPERTIES AND SYNAPTIC RESPONSES OF RAT STRIATAL NEURONS INVITRO {1991} JOURNAL OF PHYSIOLOGY-LONDON
    Vol. {443}, pp. {533-553} 
    article  
    Abstract: 1. A tissue slice containing a section of striatum was cut obliquely from rat brain so as to preserve adjacent cortex and pallidum. Intracellular recordings were made from 368 neurones, using either conventional or tight-seal configurations. 2. Two types of neurone were distinguished electrophysiologically. Principal cells (96 had very negative resting potentials (-89 mV) and a low input resistance at the resting membrane potential (39 M-OMEGA): membrane conductance (10 nS at -65 mV) increased within tens of milliseconds after the onset of hyperpolarization (99 nS at -120 mV). Secondary cells (4 had less negative resting potentials (-60 mV) and a higher input resistance (117 M-OMEGA at the resting potential): hyperpolarization caused an inward current to develop over hundreds of milliseconds that had the properties of H-current. 3. Most principal cells were activated antidromically by electrical stimulation of the globus pallidus or internal capsule. Intracellular labelling with biocytin showed that principal cells had a medium sized soma (10-18-mu-m), extensive dendritic trees densely studded with spines and, in some cases, a main axon which extended towards the globus pallidus. 4. Electrical stimulation of the corpus callosum or external capsule evoked a depolarizing postsynaptic potential. This synaptic potential was reversibly blocked by a combination of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10-mu-m) and DL-2-amino-5-phosphonovaleric acid (APV, 30-mu-M), but was unaffected by bicuculline (30-mu-M) and picrotoxin (100-mu-M). The underlying synaptic current had a fast component (time to peak about 4 ms), the amplitude of which was linearly related to membrane potential and which was blocked by CNQX; in CNQX the synaptic current had a slower component (time to peak about 10 ms) which showed voltage dependence typical of N-methyl-D-aspartate (NMDA) receptors. Both currents reversed at -5 mV. 5. Focal electrical stimulation within the striatum (100-300-mu-m from the site of intracellular recording) evoked a synaptic potential that was partially blocked (45-95 by CNQX and APV: the remaining synaptic potential was blocked by bicuculline (30-mu-M). The bicuculline-sensitive synaptic current reversed at the chloride equilibrium potential. 6. The findings confirm that the majority of neostriatal neurones (principal cells, medium spiny neurones) project to the pallidum and receive synaptic inputs from cerebral cortex mediated by an excitatory amino acid acting through NMDA and non-NMDA receptors. These cells also receive synaptic inputs from intrinsic striatal neurones mediated by GABA. A minority of cells (4 have distinct electrophysiological properties, also receive both types of synaptic input, and are presumed to be interneurones.
    BibTeX:
    @article{JIANG1991,
      author = {JIANG, ZG and NORTH, RA},
      title = {MEMBRANE-PROPERTIES AND SYNAPTIC RESPONSES OF RAT STRIATAL NEURONS INVITRO},
      journal = {JOURNAL OF PHYSIOLOGY-LONDON},
      year = {1991},
      volume = {443},
      pages = {533-553}
    }
    
    JOHNSON, S. & NORTH, R. OPIOIDS EXCITE DOPAMINE NEURONS BY HYPERPOLARIZATION OF LOCAL INTERNEURONS {1992} JOURNAL OF NEUROSCIENCE
    Vol. {12}({2}), pp. {483-488} 
    article  
    Abstract: Increased activity of dopamine-containing neurons in the ventral tegmental area is necessary for the reinforcing effects of opioids and other abused drugs. Intracellular recordings from these cells in slices of rat brain in vitro showed that opioids do not affect the principal (dopamine-containing) neurons but hyperpolarize secondary (GABA-containing) interneurons. Experiments with agonists and antagonists selective for opioid receptor subtypes indicated that the hyperpolarization of secondary cells involved the mu-receptor. Most principal cells showed spontaneous bicuculline-sensitive synaptic potentials when the extracellular potassium concentration was increased from 2.5 to 6.5 or 10.5 mM; these were prevented by TTX and assumed to result from action potentials arising in slightly depolarized local interneurons. The frequency of these synaptic potentials, but not their amplitudes, was reduced by opioids selective for mu-receptors. It is concluded that hyperpolarization of the interneurons by opioids reduces the spontaneous GABA-mediated synaptic input to the dopamine cells. In vivo, this would lead to excitation of the dopamine cells by disinhibition, which would be expected to contribute to the positive reinforcement seen with mu-receptor agonists such as morphine and heroin.
    BibTeX:
    @article{JOHNSON1992,
      author = {JOHNSON, SW and NORTH, RA},
      title = {OPIOIDS EXCITE DOPAMINE NEURONS BY HYPERPOLARIZATION OF LOCAL INTERNEURONS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1992},
      volume = {12},
      number = {2},
      pages = {483-488}
    }
    
    JOHNSON, S. & NORTH, R. 2 TYPES OF NEURON IN THE RAT VENTRAL TEGMENTAL AREA AND THEIR SYNAPTIC INPUTS {1992} JOURNAL OF PHYSIOLOGY-LONDON
    Vol. {450}, pp. {455-468} 
    article  
    Abstract: 1. Intracellular recordings were made from 241 ventral tegmental neurones in slices of rat midbrain. Seventy-seven per cent of neurones were hyperpolarized by dopamine (principal cells); 16% were hyperpolarized by opioid peptides (secondary cells). 2. Most principal cells fired spontaneously (1-3 Hz) with a threshold of -53 mV; most secondary cells did not fire spontaneously. Action potentials of principal cells were longer (0.9 ms) than those of secondary cells (0.5 ms). 3. Focal electrical stimulation within the ventral tegmental area evoked a biphasic synaptic potential, depolarization followed by hyperpolarization, with a duration of about 200 ms. Experiments with receptor antagonists showed that the depolarizing component resulted from activation of both N-methyl-D-aspartate (NMDA) and non-NMDA receptors and the hyperpolarizing component resulted from activation of GABA(A) receptors. 4. A later hyperpolarizing synaptic potential developed after a latency of 50 ms, reached its peak in 250 ms and had a duration of about 1 s. It reversed polarity at -108 mV (external potassium concentration was 2.5 mM), was blocked by phaclofen (30-mu-M-1 mM) or 2-hydroxysaclofen (100-300-mu-M). In some cells, a phaclofen-resistant component remained that was increased by cocaine and blocked by sulpiride (1-mu-M). 5. It is concluded that the ventral tegmental area contains two types of neurone having properties similar to those in the substantia nigra. The cells receive synaptic inputs mediated by excitatory amino acids acting at NMDA and non-NMDA receptors, GABA acting at GABA(A) and GABA(B) receptors, and dopamine acting at D2 receptors.
    BibTeX:
    @article{JOHNSON1992a,
      author = {JOHNSON, SW and NORTH, RA},
      title = {2 TYPES OF NEURON IN THE RAT VENTRAL TEGMENTAL AREA AND THEIR SYNAPTIC INPUTS},
      journal = {JOURNAL OF PHYSIOLOGY-LONDON},
      year = {1992},
      volume = {450},
      pages = {455-468}
    }
    
    JONES, D., MOGESON, G. & WU, M. INJECTIONS OF DOPAMINERGIC, CHOLINERGIC, SEROTONINERGIC AND GABAERGIC DRUGS INTO THE NUCLEUS ACCUMBENS - EFFECTS ON LOCOMOTOR-ACTIVITY IN THE RAT {1981} NEUROPHARMACOLOGY
    Vol. {20}({1}), pp. {29-37} 
    article  
    BibTeX:
    @article{JONES1981,
      author = {JONES, DL and MOGESON, GJ and WU, M},
      title = {INJECTIONS OF DOPAMINERGIC, CHOLINERGIC, SEROTONINERGIC AND GABAERGIC DRUGS INTO THE NUCLEUS ACCUMBENS - EFFECTS ON LOCOMOTOR-ACTIVITY IN THE RAT},
      journal = {NEUROPHARMACOLOGY},
      year = {1981},
      volume = {20},
      number = {1},
      pages = {29-37}
    }
    
    JONES, G., HERNANDEZ, T., KENDALL, D., MARSDEN, C. & ROBBINS, T. DOPAMINERGIC AND SEROTONERGIC FUNCTION FOLLOWING ISOLATION REARING IN RATS - STUDY OF BEHAVIORAL-RESPONSES AND POSTMORTEM AND INVIVO NEUROCHEMISTRY {1992} PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
    Vol. {43}({1}), pp. {17-35} 
    article  
    Abstract: This series of experiments compared isolation-reared and socially reared rats for their locomotor activity, behavioural stereotypy, and monoamine function both postmortem and in vivo using intracerebral dialysis. In Experiment 1, isolates showed an altered time course of locomotor activity following d-amphetamine sulphate (AMPH) administration (0.5, 2.0, 3.0, or 5.0 mg/kg, SC). Isolation-reared rats also showed increased sensitivity to the sedative effects of a low dose of apomorphine hydrochloride (0.1 mg/kg) but did not differ from social controls following higher doses of the drug (0.5, 1.5, or 3.0 mg/kg, SC). Isolates showed a decrease in the intensity of apomorphine-induced stereotyped behaviours but no change in stereotypy induced by AMPH. In Experiment 2, isolates had. higher postmortem dopamine (DA) concentrations and an altered asymmetry in DA function in the medial prefrontal cortex (PFC) but not in the nucleus accumbens (NAC) or caudate putamen (CPu). Isolated rats also had a lower 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the NAC (but not in the PFC or CPu) compared to controls. Experiment 3 used intracerebral dialysis to examine monoamine function in vivo following isolation rearing. Isolates showed greater increases in extracellular DA and greater decreases in DOPAC in response to 2 mg/kg AMPH SC in both the NAC and CPu. There were no apparent differences in the perfusate concentrations of either dopamine (DA), dihydroxyphenylacetic acid (DOPAC), or homovanillic acid (HVA) prior to drug administration. However, consistent with the results of Experiment 2, isolates had a reduced basal perfusate concentration of 5-HIAA from the NAC but not from the CPu. Experiment 4 measured postsynaptic DA function in CPu tissue slices following isolation. Isolation rearing did not affect cAMP accumulation in response to stimulation of D1 DA receptors by DA (0, 2.7, 9, or 30-mu-M). In addition, isolation rearing did not affect the coupling between D1 and D2 receptors, as measured by the increase in cAMP accumulation with 1-mu-M 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-I H-3-benzazepin (SK&F 38393) and its reduction by 10-mu-M quinperole hydrochloride (LY 171555). These results are discussed in terms of the possible relationship between these neurochemical findings and the behavioural disturbances following isolation rearing of rats.
    BibTeX:
    @article{JONES1992,
      author = {JONES, GH and HERNANDEZ, TD and KENDALL, DA and MARSDEN, CA and ROBBINS, TW},
      title = {DOPAMINERGIC AND SEROTONERGIC FUNCTION FOLLOWING ISOLATION REARING IN RATS - STUDY OF BEHAVIORAL-RESPONSES AND POSTMORTEM AND INVIVO NEUROCHEMISTRY},
      journal = {PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR},
      year = {1992},
      volume = {43},
      number = {1},
      pages = {17-35}
    }
    
    Jones, S., Gainetdinov, R., Jaber, M., Giros, B., Wightman, R. & Caron, M. Profound neuronal plasticity in response to inactivation of the dopamine transporter {1998} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {95}({7}), pp. {4029-4034} 
    article  
    Abstract: The dopamine transporter (DAT) plays an important role in calibrating the duration and intensity of dopamine neurotransmission in the central nervous system, We have used a strain of mice in which the gene for the DAT has been genetically deleted to identify the DAT's homeostatic role. We find that removal of the DAT dramatically prolongs the lifetime (300 times) of extracellular dopamine, Within the time frame of neurotransmission, no other processes besides diffusion can compensate for the lack of the DAT, and the absence of the DAT produces extensive adaptive changes to control dopamine neurotransmission. Despite the absence of a clearance mechanism, dopamine extracellular levels were only 5 times greater than control animals due to a 95% reduction in content and a 75% reduction in release, Paradoxically, dopamine synthesis rates are doubled despite a decrease of 90% in the levels of tyrosine hydroxylase and degradation is markedly enhanced, Thus, the DAT not only controls the duration of extracellular dopamine signals but also plays a critical role in regulating presynaptic dopamine homeostasis. It is interesting to consider that the switch to a dopamine-deficient, but functionally hyperactive, mode of neurotransmission observed in mice lacking the DAT may represent an extreme example of neuronal plasticity resulting from long-term psychostimulant abuse.
    BibTeX:
    @article{Jones1998,
      author = {Jones, SR and Gainetdinov, RR and Jaber, M and Giros, B and Wightman, RM and Caron, MG},
      title = {Profound neuronal plasticity in response to inactivation of the dopamine transporter},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1998},
      volume = {95},
      number = {7},
      pages = {4029-4034}
    }
    
    Jones, S., Gainetdinov, R., Wightman, R. & Caron, M. Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter {1998} JOURNAL OF NEUROSCIENCE
    Vol. {18}({6}), pp. {1979-1986} 
    article  
    Abstract: Amphetamine (AMPH) inhibits uptake and causes release of dopamine (DA) from presynaptic terminals. AMPH can act on both vesicular storage of DA and directly on the dopamine transporter (DAT). To assess the relative importance of these two processes, we have examined the releasing actions of AMPH in mice with a genetic deletion of the DAT. The sequence of actions of AMPH has been determined by following the real time changes of DA in the extracellular fluid of intact tissue with fast scan cyclic voltammetry. In striatal slices from wild-type mice, AMPH causes a gradual (similar to 30 min) increase in extracellular DA, with a concomitant disappearance of the pool of DA available for depolarization-evoked release. Conversely, in slices from mice lacking the DAT, although a similar disappearance of electrically stimulated DA release occurs, extracellular DA does not increase. Similarly, microdialysis measurements of DA after AMPH in freely moving animals show no change in mice lacking the DAT, whereas it increases 10-fold in wild-type mice. In contrast, redistribution of DA from vesicles to the cytoplasm by the use of a reserpine-like compound, Ro4-1284, does not increase extracellular DA in slices from wild-type animals; however, subsequent addition of AMPH induces rapid (<5 min) release of DA. Thus, the DAT is required for the releasing action, but not the vesicle-depleting action, of AMPH on DA neurons, and the latter represents the rate-limiting step in the effects of AMPH. Furthermore, these findings suggest that in the absence of pharmacological manipulation, such as the use of amphetamine, endogenous cytoplasmic DA normally does not reach sufficient concentrations to reverse the DAT.
    BibTeX:
    @article{Jones1998a,
      author = {Jones, SR and Gainetdinov, RR and Wightman, RM and Caron, MG},
      title = {Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1998},
      volume = {18},
      number = {6},
      pages = {1979-1986}
    }
    
    JOYCE, J., SHANE, A., LEXOW, N., WINOKUR, A., CASANOVA, M. & KLEINMAN, J. SEROTONIN UPTAKE SITES AND SEROTONIN RECEPTORS ARE ALTERED IN THE LIMBIC SYSTEM OF SCHIZOPHRENICS {1993} NEUROPSYCHOPHARMACOLOGY
    Vol. {8}({4}), pp. {315-336} 
    article  
    Abstract: Serotonin (5-HT) uptake sites were mapped by autoradiographic means with [H-3]cyano-imipramine ([H-3]CN-IMI), the 5-HT1A receptor with [H-3]8-hydroxy-2-[di-n-propyl-amino]tetralin ([H-3]8-OH-DPAT), and the 5-HT2 receptor with both [H-3]ketanserin and [I-125]lysergic acid diethylamide ([I-125]LSD) in eight nonneurologic controls and 10 cases with a diagnosis of schizophrenia. In the striatum, there was a marked heterogeneous patterning of 5-HT uptake sites that corresponded to the striosomal/matrix compartmentalization of the striatum. This organization was not matched with an equally heterogeneous pattern of either 5-HT2 or 5-HT1A receptors. For the isocortex, a general organizational scheme was observed with the 5-HT1A receptor expression high in the external laminae and deep laminae, but 5-HT2 receptor expression was higher in the internal laminae. There was a laminar distribution of 5-HT uptake sites that approximated the combined distributions of the 5-HT1A receptor and the 5-HT2 receptor. In the parahippocampal gyrus and hippocampus, the distribution of 5-HT uptake sites was complementary to the distribution of 5-HT1A and 5-HT2 receptors. In schizophrenic cases, there was a large increase in the number and altered striosomal/matrix organization of 5-HT uptake sites in the striatum. There was also an increase in the numbers of 5-HT2 receptors in the nucleus accumbens and ventral putamen of the schizophrenics. The number of 5-HT1A receptors was not modified. There was a marked reduction in 5-HT uptake sites in the external and middle laminae of the anterior cingulate, frontal cortex, and posterior cingulate, and no changes were observed in the motor cortex, temporal cortex, or hippocampus. Increased numbers of 5-HT1A receptors were found in the posterior cingulate, motor cortex, and hippocampus. Serotonin2 receptors were substantially elevated in the posterior cingulate, temporal cortex, and hippocampus, but not in the frontal, anterior cingulate, or motor cortices. Examination of the temporal lobe and hippocampus of a group of nonschizophrenic suicides (n = 8) indicated the alterations in 5-HT system in the limbic regions of the striatum, the limbic cortex, and hippocampus of the schizophrenic cases may be disease specific.
    BibTeX:
    @article{JOYCE1993,
      author = {JOYCE, JN and SHANE, A and LEXOW, N and WINOKUR, A and CASANOVA, MF and KLEINMAN, JE},
      title = {SEROTONIN UPTAKE SITES AND SEROTONIN RECEPTORS ARE ALTERED IN THE LIMBIC SYSTEM OF SCHIZOPHRENICS},
      journal = {NEUROPSYCHOPHARMACOLOGY},
      year = {1993},
      volume = {8},
      number = {4},
      pages = {315-336}
    }
    
    KALIVAS, P. & ALESDATTER, J. INVOLVEMENT OF N-METHYL-D-ASPARTATE RECEPTOR STIMULATION IN THE VENTRAL TEGMENTAL AREA AND AMYGDALA IN BEHAVIORAL SENSITIZATION TO COCAINE {1993} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {267}({1}), pp. {486-495} 
    article  
    Abstract: Systemic administration of N-methyl-D-aspartate (NMDA) antagonists prevents the development of behavioral sensitization to amphetamine-like psychostimulants. Pretreatment with the non-competitive NMDA antagonist, MK-801, resulted in a dose-dependent blockade of behavioral sensitization to cocaine. However, pretreatment with the highest dose of MK-801 (0.25 mg/kg i.p.) alone inhibited the behavioral response to a subsequent cocaine challenge 24 hr later. The induction of behavioral sensitization is known to result, at least partly, from an action by psychostimulants in the ventral tegmental area (VTA). To determine wheter the dose-dependent inhibition of behavioral sensitization to cocaine by NMDA antagonists resulted from receptor blockade in the VTA, rats were pretreated in the VTA with the MK-801 or the competitive NMDA antagonist, 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid, before systemically administered cocaine (30 mg/kg i.p.). Two to 3 days later rats were challenged with cocaine alone (1 5 mg/kg i. p.). Pretreatment with either NMDA antagonist into the VTA prevented the manifestation of behavioral sensitization. Intracranial pretreatment with MK-801 was also made into the nucleus accumbens and amygdala which have been implicated in psychostimulant-induced sensitization. Whereas MK-801 was without effect in the nucleus accumbens, when microinjected into the ventral amygdala it prevented the manifestation of behavioral sensitization to a cocaine challenge. The blockade of sensitization by MK-801 in the VTA was produced with a minimum effective dose of 0.01 nmol, whereas the minimum effective dose in the amygdala was 1.0 nmol. These data demonstrate that stimulation of NMDA receptors in the VTA and amygdala is necessary in the development of behavioral sensitization to cocaine.
    BibTeX:
    @article{KALIVAS1993b,
      author = {KALIVAS, PW and ALESDATTER, JE},
      title = {INVOLVEMENT OF N-METHYL-D-ASPARTATE RECEPTOR STIMULATION IN THE VENTRAL TEGMENTAL AREA AND AMYGDALA IN BEHAVIORAL SENSITIZATION TO COCAINE},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1993},
      volume = {267},
      number = {1},
      pages = {486-495}
    }
    
    KALIVAS, P. & DUFFY, P. SELECTIVE ACTIVATION OF DOPAMINE TRANSMISSION IN THE SHELL OF THE NUCLEUS-ACCUMBENS BY STRESS {1995} BRAIN RESEARCH
    Vol. {675}({1-2}), pp. {325-328} 
    article  
    Abstract: A microdialysis probe was placed in either the shell or core compartment of the nucleus accumbens and rats were exposed to mild footshock. Extracellular dopamine levels in the shell of the nucleus accumbens were elevated during the 20-min collection period immediately after discontinuing footshock. In contrast, the levels of dopamine remained unaltered in the core of the nucleus accumbens.
    BibTeX:
    @article{KALIVAS1995,
      author = {KALIVAS, PW and DUFFY, P},
      title = {SELECTIVE ACTIVATION OF DOPAMINE TRANSMISSION IN THE SHELL OF THE NUCLEUS-ACCUMBENS BY STRESS},
      journal = {BRAIN RESEARCH},
      year = {1995},
      volume = {675},
      number = {1-2},
      pages = {325-328}
    }
    
    KALIVAS, P. & DUFFY, P. TIME COURSE OF EXTRACELLULAR DOPAMINE AND BEHAVIORAL SENSITIZATION TO COCAINE .1. DOPAMINE AXON TERMINALS {1993} JOURNAL OF NEUROSCIENCE
    Vol. {13}({1}), pp. {266-275} 
    article  
    Abstract: Repeated administration of cocaine to rodents produces a progressive augmentation in motor activity known as behavioral sensitization. By using microdialysis in the ventral striatum, some studies have found that the development of behavioral sensitization is associated with a similar augmentation in dopamine release, while others have not. It was postulated that differences in doses and withdrawal periods may account for the discrepancies between studies. Rats were behaviorally sensitized to daily peripheral injections using two cocaine treatment regimens (15 mg/kg, i.p. x 5 d or 30 mg/kg, i.p. x 5 d). Using in vivo microdialysis in the ventral striatum, the effect of acute cocaine (1 5 mg/kg, i.p.) on extracellular dopamine content and motor behavior was examined at various times after discontinuing daily treatments. Twenty-four hours after discontinuing the low dose of daily cocaine, the increase in motor activity and extracellular dopamine elicited by an acute cocaine challenge was significantly elevated. In contrast, following the higher daily treatment regimen there was a significant augmentation in motor activity, but the increase in extracellular dopamine produced by cocaine was significantly reduced. When rats were challenged 10-14 d after discontinuing either dosage regimen of daily cocaine, the increase in both motor activity and extracellular dopamine was augmented. In general, the increase in extracellular dopamine by an acute cocaine challenge increased over time when rats were challenged between 1 and 22 d after discontinuing daily cocaine. Basal concentrations of extracellular dopamine were determined by measuring the in vivo flux of dopamine across the dialysis membrane, and there was no significant difference at 24 hr or 2 weeks following the last daily injection of saline or cocaine. It is concluded that behavioral sensitization to cocaine is generally associated with an augmentation in extracellular dopamine in the ventral striatum, but that high doses of daily cocaine produce apparent tolerance to the augmentation in extracellular dopamine during the early withdrawal period.
    BibTeX:
    @article{KALIVAS1993,
      author = {KALIVAS, PW and DUFFY, P},
      title = {TIME COURSE OF EXTRACELLULAR DOPAMINE AND BEHAVIORAL SENSITIZATION TO COCAINE .1. DOPAMINE AXON TERMINALS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1993},
      volume = {13},
      number = {1},
      pages = {266-275}
    }
    
    KALIVAS, P. & DUFFY, P. EFFECT OF ACUTE AND DAILY COCAINE TREATMENT ON EXTRACELLULAR DOPAMINE IN THE NUCLEUS ACCUMBENS {1990} SYNAPSE
    Vol. {5}({1}), pp. {48-58} 
    article  
    BibTeX:
    @article{KALIVAS1990,
      author = {KALIVAS, PW and DUFFY, P},
      title = {EFFECT OF ACUTE AND DAILY COCAINE TREATMENT ON EXTRACELLULAR DOPAMINE IN THE NUCLEUS ACCUMBENS},
      journal = {SYNAPSE},
      year = {1990},
      volume = {5},
      number = {1},
      pages = {48-58}
    }
    
    Kalivas, P. & McFarland, K. Brain circuitry and the reinstatement of cocaine-seeking behavior {2003} PSYCHOPHARMACOLOGY
    Vol. {168}({1-2}), pp. {44-56} 
    article DOI  
    Abstract: Rationale. Recent studies have attempted to identify the neuroanatomical substrates underlying primed reinstatement of drug-seeking behavior. Identification of neuronal substrates will provide a logical rationale for designing pharmacological interventions in treating drug relapse. Objective. The objective was to identify brain circuitry that is shared between cue-, drug- and stress-primed reinstatement, as well as identifying aspects of brain circuitry that are distinct for each stimulus modality. The resulting circuit offers theoretical interpretations for consideration in future studies. Results. Aspects of the circuitry mediating reinstatement can be identified with reasonable confidence. The role of the basolateral amygdala in cue-primed reinstatement, the role of the ventral tegmental area in drug-primed reinstatement and the role of adrenergic innervation of the extended amygdala in stress-primed reinstatement are well characterized. Also, all three modes for priming reinstatement may converge on the anterior cingulate cortex and have a final common output through the core of the nucleus accumbens. Lacunae in our understanding of the circuit were identified, especially with regard to how stress priming is conveyed from the extended amygdala to the shared anterior cingulate accumbens core circuit. Conclusions. The proposed convergence of priming stimuli into the glutamatergic projection from anterior cingulate to the accumbens core combined with the changes in glutamate transmission and signaling that accompany repeated psychostimulant administration points to the potential value of pharmacological agents that manipulate glutamate release or postsynaptic glutamate receptor signaling and trafficking in treating primed relapse in addicts.
    BibTeX:
    @article{Kalivas2003,
      author = {Kalivas, PW and McFarland, K},
      title = {Brain circuitry and the reinstatement of cocaine-seeking behavior},
      journal = {PSYCHOPHARMACOLOGY},
      year = {2003},
      volume = {168},
      number = {1-2},
      pages = {44-56},
      doi = {{10.1007/s00213-003-1393-2}}
    }
    
    KALIVAS, P., SORG, B. & HOOKS, M. THE PHARMACOLOGY AND NEURAL CIRCUITRY OF SENSITIZATION TO PSYCHOSTIMULANTS {1993} BEHAVIOURAL PHARMACOLOGY
    Vol. {4}({4}), pp. {315-334} 
    article  
    Abstract: Behavioral sensitization to amphetamine-like psychostimulants is manifest as a progressive increase in drug-induced anxiety and paranoia which can culminate in psychopathologies, such as paranoid psychosis and panic attacks. Sensitization may also mediate the facilitation of drug relapse in addicts by increasing the reinforcing value of acute drug administration. The primary animal model for psychostimulant-induced psychopathologies involves repeated, non-contingent administration of drug to rodents, which can produce a progressive and enduring augmentation in motor activity and increased susceptibility to drug self-administration. Because of the mature literature implicating mesoaccumbens dopamine transmission in the acute motor and reinforcing effects of amphetamine-like stimulants, investigation into the neural basis of behavioral sensitization has focused on this projection. Over the last decade, with a few exceptions, the neurochemical and molecular literature that has emerged from this effort is replete with inconsistencies. In contrast, the presence of behavioral sensitization is a highly replicable event. It is proposed that behavioral sensitization arises from an alteration in the neural circuitry that subserves the translation of motivationally relevant stimuli into adaptive motor responses. The mesoaccumbens dopamine projection is embedded in this circuit and an enduring change in dopamine transmission may alter the functional state of the circuit to produce behavioral sensitization. However, combinations of alterations in other connections within the circuit can also support behavioral sensitization. The specific changes in the circuit that promote behavioral sensitization are under the control of experimental parameters, such as the drug employed, dosage regimen, withdrawal period and the presence of conditioning cues. Thus, the profile of neurochemical alterations observed after exposure to repeated psychostimulants may vary depending upon the experimental protocol and strain of animals, even though all laboratories report the presence of behavioral sensitization.
    BibTeX:
    @article{KALIVAS1993a,
      author = {KALIVAS, PW and SORG, BA and HOOKS, MS},
      title = {THE PHARMACOLOGY AND NEURAL CIRCUITRY OF SENSITIZATION TO PSYCHOSTIMULANTS},
      journal = {BEHAVIOURAL PHARMACOLOGY},
      year = {1993},
      volume = {4},
      number = {4},
      pages = {315-334}
    }
    
    KALIVAS, P. & STEWART, J. DOPAMINE TRANSMISSION IN THE INITIATION AND EXPRESSION OF DRUG-INDUCED AND STRESS-INDUCED SENSITIZATION OF MOTOR-ACTIVITY {1991} BRAIN RESEARCH REVIEWS
    Vol. {16}({3}), pp. {223-244} 
    article  
    Abstract: Progress has been made over the last 10 years in determining the neural mechanisms of sensitization induced by amphetamine-like psychostimulants, opioids and stressors. Changes in dopamine transmission in axon terminal fields such as the nucleus accumbens appear to underlie the expression of sensitization, but the actions of drugs and stressors in the somatodendritic regions of the A10/A9 dopamine neurons seem critical for the initiation of sensitization. Manipulations that increase somatodendritic dopamine release and permit the stimulation of D1 dopamine receptors in this region induce changes in the dopamine system that lead to the development of long-term sensitization. However, it is not known exactly how the changes in the A10/A9 region are encoded to permit augmented dopamine transmission in the terminal field. One possibility is that the dopamine neurons of sensitized animals have become increasingly sensitive to excitatory pharmacological and environmental stimuli or desensitized to inhibitory regulation. Alternatively, changes in cellular activity or protein synthesis may result in a change in the presynaptic regulation of axon terminal dopamine release.
    BibTeX:
    @article{KALIVAS1991,
      author = {KALIVAS, PW and STEWART, J},
      title = {DOPAMINE TRANSMISSION IN THE INITIATION AND EXPRESSION OF DRUG-INDUCED AND STRESS-INDUCED SENSITIZATION OF MOTOR-ACTIVITY},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {1991},
      volume = {16},
      number = {3},
      pages = {223-244}
    }
    
    Kalivas, P. & Volkow, N. The neural basis of addiction: A pathology of motivation and choice {2005} AMERICAN JOURNAL OF PSYCHIATRY
    Vol. {162}({8}), pp. {1403-1413} 
    article  
    Abstract: Objective: A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding. Method: Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking. Results: While dopamine is critical for acute reward and initiation of addiction, end-stage addiction results primarily from cellular adaptations in anterior cingulate and orbitofrontal glutamatergic projections to the nucleus accumbens. Pathophysiological plasticity in excitatory transmission reduces the capacity of the prefrontal cortex to initiate behaviors in response to biological rewards and to provide executive control over drug seeking. Simultaneously, the prefrontal cortex is hyperresponsive to stimuli predicting drug availability, resulting in supraphysiological glutamatergic drive in the nucleus accumbens, where excitatory synapses have a reduced capacity to regulate neurotransmission. Conclusions: Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control ( choice), and enhancing glutamatergic drive in response to drug-associated stimuli.
    BibTeX:
    @article{Kalivas2005,
      author = {Kalivas, PW and Volkow, ND},
      title = {The neural basis of addiction: A pathology of motivation and choice},
      journal = {AMERICAN JOURNAL OF PSYCHIATRY},
      year = {2005},
      volume = {162},
      number = {8},
      pages = {1403-1413},
      note = {157th Annual Meeting of the American-Psychiatric-Association, New York, NY, MAY 01-06, 2004}
    }
    
    Kalivas, P., Volkow, N. & Seamans, J. Unmanageable motivation in addiction: A pathology in prefrontal-accumbens glutamate transmission {2005} NEURON
    Vol. {45}({5}), pp. {647-650} 
    article DOI  
    BibTeX:
    @article{Kalivas2005a,
      author = {Kalivas, PW and Volkow, N and Seamans, J},
      title = {Unmanageable motivation in addiction: A pathology in prefrontal-accumbens glutamate transmission},
      journal = {NEURON},
      year = {2005},
      volume = {45},
      number = {5},
      pages = {647-650},
      doi = {{10.1016/j.neurons.2005.02.005}}
    }
    
    Kapur, S. Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia {2003} AMERICAN JOURNAL OF PSYCHIATRY
    Vol. {160}({1}), pp. {13-23} 
    article  
    Abstract: Objective: The clinical hallmark of schizophrenia is psychosis. The objective of this overview is to link the neurobiology (brain), the phenomenological experience (mind), and pharmacological aspects of psychosisin-schizophrenia into a unitary framework. Method: Current ideas regarding the neurobiology and phenomenology of psychosis and schizophrenia, the role of dopamine, and the mechanism of action of antipsychotic medication were integrated to develop this framework. Results: A central role of dopamine is to mediate the ``salience'' of environmental events and internal representations. It is proposed that a dysregulated, hyperdopaminergic state, at a ``brain'' level of description and analysis, leads to an aberrant assignment of salience to the elements of one's experience, at a ``mind'' level. Delusions are a cognitive effort by the patient to make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. Antipsychotics ``dampen the salience'' of these abnormal experiences and by doing so permit the resolution of symptoms. The antipsychotics do not erase the symptoms but provide the platform for a process of psychological resolution. However, if antipsychotic treatment is stopped, the dysregulated neurochemistry returns, the dormant ideas and experiences become reinvested with aberrant salience, and a relapse occurs. Conclusions: The article provides a heuristic framework for linking the psychological and biological in psychosis. Predictions of this hypothesis, particularly regarding the possibility of synergy between psychological and pharmacological therapies, are presented. The author describes how the hypothesis is complementary to other ideas about psychosis and also discusses its limitations.
    BibTeX:
    @article{Kapur2003,
      author = {Kapur, S},
      title = {Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia},
      journal = {AMERICAN JOURNAL OF PSYCHIATRY},
      year = {2003},
      volume = {160},
      number = {1},
      pages = {13-23}
    }
    
    Karreman, M. & Moghaddam, B. The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: An effect mediated by ventral tegmental area {1996} JOURNAL OF NEUROCHEMISTRY
    Vol. {66}({2}), pp. {589-598} 
    article  
    Abstract: The present study examined whether the prefrontal cortex (PFC) exerts a tonic control over the basal release of dopamine in the limbic striatum and whether this control is mediated by glutamatergic afferents to the dopamine cell body or terminal regions. Using intracerebral microdialysis in freely moving rats, it was demonstrated that application of tetrodotoxin in the contralateral PFC significantly decreased the release of dopamine in the medial striatum. Conversely, blockade of the tonic inhibitory GABAergic input in the PFC with bicuculline increased the release of dopamine in the medial striatum. Application of excitatory amino acid receptor antagonists into the striatum, while bicuculline was perfused in the PFC, did not affect the bicuculline-evoked dopamine increase in the striatum, However, infusion of tetrodotoxin or excitatory amino acid receptor antagonists into the ventral tegmental area, a region containing dopamine cell bodies that project to the medial striatum, blocked the stimulation of striatal dopamine release induced by infusion of bicuculline into the PFC, These data demonstrate that the basal output of dopamine terminals in the medial striatum is under a tonic excitatory control of the PFC, Furthermore, this control occurs primarily through glutamatergic projections to the dopamine cell body area rather than the terminal regions.
    BibTeX:
    @article{Karreman1996,
      author = {Karreman, M and Moghaddam, B},
      title = {The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: An effect mediated by ventral tegmental area},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1996},
      volume = {66},
      number = {2},
      pages = {589-598}
    }
    
    Katona, I., Rancz, E., Acsady, L., Ledent, C., Mackie, K., Hajos, N. & Freund, T. Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission {2001} JOURNAL OF NEUROSCIENCE
    Vol. {21}({23}), pp. {9506-9518} 
    article  
    Abstract: Cannabinoids are the most popular illicit drugs used for recreational purposes worldwide. However, the neurobiological substrate of their mood-altering capacity has not been elucidated so far. Here we report that CB1 cannabinoid receptors are expressed at high levels in certain amygdala nuclei, especially in the lateral and basal nuclei, but are absent in other nuclei (e.g., in the central nucleus and in the medial nucleus). Expression of the CB1 protein was restricted to a distinct subpopulation of GABAergic interneurons corresponding to large cholecystokinin-positive cells. Detailed electron microscopic investigation revealed that CB1 receptors are located presynaptically on cholecystokinin-positive axon terminals, which establish symmetrical GABAergic synapses with their postsynaptic targets. The physiological consequence of this particular anatomical localization was investigated by whole-cell patch-clamp recordings in principal cells of the lateral and basal nuclei. CB1 receptor agonists WIN 55,212-2 and CP 55,940 reduced the amplitude of GABA(A) receptor-mediated evoked and spontaneous IPSCs, whereas the action potential-independent miniature IPSCs were not significantly affected. In contrast, CB1 receptor agonists were ineffective in changing the amplitude of IPSCs in the rat central nucleus and in the basal nucleus of CB1 knock-out mice. These results suggest that cannabinoids target specific elements in neuronal networks of given amygdala nuclei, where they presynaptically modulate GABAergic synaptic transmission. We propose that these anatomical and physiological features, characteristic of CB1 receptors in several forebrain regions, represent the neuronal substrate for endocannabinoids involved in retrograde synaptic signaling and may explain some of the emotionally relevant behavioral effects of cannabinoid exposure.
    BibTeX:
    @article{Katona2001,
      author = {Katona, I and Rancz, EA and Acsady, L and Ledent, C and Mackie, K and Hajos, N and Freund, TF},
      title = {Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2001},
      volume = {21},
      number = {23},
      pages = {9506-9518}
    }
    
    Kauer, J.A. & Malenka, R.C. Synaptic plasticity and addiction {2007} NATURE REVIEWS NEUROSCIENCE
    Vol. {8}({11}), pp. {844-858} 
    article DOI  
    Abstract: Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems.
    BibTeX:
    @article{Kauer2007,
      author = {Kauer, Julie A. and Malenka, Robert C.},
      title = {Synaptic plasticity and addiction},
      journal = {NATURE REVIEWS NEUROSCIENCE},
      year = {2007},
      volume = {8},
      number = {11},
      pages = {844-858},
      doi = {{10.1038/nrn2234}}
    }
    
    Kelley, A. Memory and addiction: Shared neural circuitry and molecular mechanisms {2004} NEURON
    Vol. {44}({1}), pp. {161-179} 
    article  
    Abstract: An important conceptual advance in the past decade has been the understanding that the process of drug addiction shares striking commonalities with neural plasticity associated with natural reward learning and memory. Basic mechanisms involving dopamine, glutamate, and their intracellular and genomic targets have been the focus of attention in this research area. These two neurotransmitter systems, widely distributed in many regions of cortex, limbic system, and basal ganglia, appear to play a key integrative role in motivation, learning, and memory, thus modulating adaptive behavior. However, many drugs of abuse exert their primary effects precisely on these pathways and are able to induce enduring cellular alterations in motivational networks, thus leading to maladaptive behaviors. Current theories and research on this topic are reviewed from an integrative systems perspective, with special emphasis on cellular, molecular, and behavioral aspects of dopamine D-1 and glutamate NMDA signaling, instrumental learning, and drug cue conditioning.
    BibTeX:
    @article{Kelley2004,
      author = {Kelley, AE},
      title = {Memory and addiction: Shared neural circuitry and molecular mechanisms},
      journal = {NEURON},
      year = {2004},
      volume = {44},
      number = {1},
      pages = {161-179}
    }
    
    Kelley, A. Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning {2004} NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
    Vol. {27}({8}), pp. {765-776} 
    article DOI  
    Abstract: The nucleus accumbens is a brain region that participates in the control of behaviors related to natural reinforcers, such as ingestion, sexual behavior, incentive and instrumental learning, and that also plays a role in addictive processes. This paper comprises a review of work from our laboratory that focuses on two main research areas: (i) the role of the nucleus accumbens in food motivation, and (ii) its putative functions in cellular plasticity underlying appetitive learning. First, work within a number of different behavioral paradigms has shown that accumbens neurochemical systems play specific and dissociable roles in different aspects of food seeking and food intake, and part of this function depends on integration with the lateral hypothalamus and amygdala. We propose that the nucleus accumbens integrates information related to cognitive, sensory, and emotional processing with hypothalamic mechanisms mediating energy balance. This system as a whole enables complex hierarchical control of adaptive ingestive behavior. Regarding the second research area, our studies examining acquisition of lever-pressing for food in rats have shown that activation of glutamate N-methyl-D-aspartate (NMDA) receptors, within broadly distributed but interconnected regions (nucleus accumbens core, posterior striatum, prefrontal cortex, basolateral and central amygdala), is critical for such learning to occur. This receptor stimulation triggers intracellular cascades that involve protein phosphorylation and new protein synthesis. It is hypothesized that activity in this distributed network (including D1 receptor activity) computes coincident events and thus enhances the probability that temporally related actions and events (e.g. lever pressing and delivery of reward) become associated. Such basic mechanisms of plasticity within this reinforcement learning network also appear to be profoundly affected in addiction. (C) 2003 Elsevier Ltd. All rights reserved.
    BibTeX:
    @article{Kelley2004a,
      author = {Kelley, AE},
      title = {Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning},
      journal = {NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS},
      year = {2004},
      volume = {27},
      number = {8},
      pages = {765-776},
      note = {Symposium on Foundations and Innovations in the Neuroscience of Drug Abuse, BETHESDA, MARYLAND, MAY 14-15, 2003},
      doi = {{10.1016/j.neubiorev.2003.11.015}}
    }
    
    Kelley, A., Bakshi, V., Haber, S., Steininger, T., Will, M. & Zhang, M. Opioid modulation of taste hedonics within the ventral striatum {2002} PHYSIOLOGY & BEHAVIOR
    Vol. {76}({3, Sp. Iss. SI}), pp. {365-377} 
    article  
    Abstract: There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food `pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modem times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity. (C) 2002 Elsevier Science Inc. All rights reserved.
    BibTeX:
    @article{Kelley2002a,
      author = {Kelley, AE and Bakshi, VP and Haber, SN and Steininger, TL and Will, MJ and Zhang, M},
      title = {Opioid modulation of taste hedonics within the ventral striatum},
      journal = {PHYSIOLOGY & BEHAVIOR},
      year = {2002},
      volume = {76},
      number = {3, Sp. Iss. SI},
      pages = {365-377},
      note = {Annual Meeting of the Society-for-the-Study-of-Ingestive-Behavior, PHILADELPHIA, PENNSYLVANIA, JUN 26-30, 2001}
    }
    
    Kelley, A., Baldo, B., Pratt, W. & Will, M. Corticostriatal-hypothalamic circuitry and food motivation: Integration of energy, action and reward {2005} PHYSIOLOGY & BEHAVIOR
    Vol. {86}({5}), pp. {773-795} 
    article DOI  
    Abstract: Work over the past decade has supported the idea that discrete aspects of appetitive motivation are differentially mediated by separate but interacting neurochemical systems within the nucleus accumbens (Acb). We review herein a series of studies in rats comparing the effects of manipulating Acb amino acid, opioid, acetylcholine, and dopamine systems on tests of free-feeding and food-reinforced operant responding. Results from our laboratory and in the literature support three general conclusions: (1) GABA output neurons localized exclusively within the Acb shell directly influence hypothalamic effector mechanisms for feeding motor patterns, but do not participate in the execution of more complex food-seeking strategies; (2) enkephalinergic neurons distributed throughout the Acb, and caudate-putamen mediate the hedonic impact of palatable (high sugar/fat) foods, and these neurons are under modulatory control by striatal cholinergic interneurons; and (3) dopamine transmission in the Acb governs general motoric and arousal processes related to response selection and invigoration, as well as motor teaming-related plasticity. These dissociations may reflect the manner in which these neurochemical systems differentially access pallido-thalamo-cortical loops reaching the voluntary motor system (in the case of opioids and dopamine), versus more restricted efferent connections to hypothalamic motor/autonomic control columns (in the case of Acb, shell GABA and glutamate systems). Moreover, we hypothesize that while these systems work in tandem to coordinate the anticipatory and consummatory phases of feeding with hypothalamic energy-sensing substrates, the striatal opioid network evolved a specialized capacity to promote overeating of energy-dense foods beyond acute homeostatic needs, to ensure an energy reserve for potential future famine. (c) 2005 Elsevier Inc. All rights reserved.
    BibTeX:
    @article{Kelley2005,
      author = {Kelley, AE and Baldo, BA and Pratt, WE and Will, MJ},
      title = {Corticostriatal-hypothalamic circuitry and food motivation: Integration of energy, action and reward},
      journal = {PHYSIOLOGY & BEHAVIOR},
      year = {2005},
      volume = {86},
      number = {5},
      pages = {773-795},
      note = {Symposium on Dietary Influences on Obesity - Environment, Behavior and Biology, W Lafayette, IN, APR 22-24, 2005},
      doi = {{10.1016/j.physbeh.2005.08.066}}
    }
    
    Kelley, A. & Berridge, K. The neuroscience of natural rewards: Relevance to addictive drugs {2002} JOURNAL OF NEUROSCIENCE
    Vol. {22}({9}), pp. {3306-3311} 
    article  
    BibTeX:
    @article{Kelley2002,
      author = {Kelley, AE and Berridge, KC},
      title = {The neuroscience of natural rewards: Relevance to addictive drugs},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2002},
      volume = {22},
      number = {9},
      pages = {3306-3311}
    }
    
    KELLEY, A. & DOMESICK, V. THE DISTRIBUTION OF THE PROJECTION FROM THE HIPPOCAMPAL-FORMATION TO THE NUCLEUS ACCUMBENS IN THE RAT - AN ANTEROGRADE-HORSERADISH AND RETROGRADE-HORSERADISH PEROXIDASE STUDY {1982} NEUROSCIENCE
    Vol. {7}({10}), pp. {2321-2335} 
    article  
    BibTeX:
    @article{KELLEY1982,
      author = {KELLEY, AE and DOMESICK, VB},
      title = {THE DISTRIBUTION OF THE PROJECTION FROM THE HIPPOCAMPAL-FORMATION TO THE NUCLEUS ACCUMBENS IN THE RAT - AN ANTEROGRADE-HORSERADISH AND RETROGRADE-HORSERADISH PEROXIDASE STUDY},
      journal = {NEUROSCIENCE},
      year = {1982},
      volume = {7},
      number = {10},
      pages = {2321-2335}
    }
    
    KELLY, P., SEVIOUR, P. & IVERSEN, S. AMPHETAMINE AND APOMORPHINE RESPONSES IN RAT FOLLOWING 6-OHDA LESIONS OF NUCLEUS ACCUMBENS SEPTI AND CORPUS STRIATUM {1975} BRAIN RESEARCH
    Vol. {94}({3}), pp. {507-522} 
    article  
    BibTeX:
    @article{KELLY1975,
      author = {KELLY, PH and SEVIOUR, PW and IVERSEN, SD},
      title = {AMPHETAMINE AND APOMORPHINE RESPONSES IN RAT FOLLOWING 6-OHDA LESIONS OF NUCLEUS ACCUMBENS SEPTI AND CORPUS STRIATUM},
      journal = {BRAIN RESEARCH},
      year = {1975},
      volume = {94},
      number = {3},
      pages = {507-522}
    }
    
    Kelz, M., Chen, J., Carlezon, W., Whisler, K., Gilden, L., Beckmann, A., Steffen, C., Zhang, Y., Marotti, L., Self, D., Tkatch, T., Baranauskas, G., Surmeier, D., Neve, R., Duman, R., Picciotto, M. & Nestler, E. Expression of the transcription factor Delta FosB in the brain controls sensitivity to cocaine {1999} NATURE
    Vol. {401}({6750}), pp. {272-276} 
    article  
    Abstract: Acute exposure to cocaine transiently induces several Fos family transcription factors in the nucleus accumbens(1), a region of the brain that is important for addiction(2,3). In contrast, chronic exposure to cocaine does not induce these proteins, but instead causes the persistent expression of highly stable isoforms of Delta FosB(4-6). Delta FoSB is also induced in the nucleus accumbens by repeated exposure to other drugs of abuse, including amphetamine, morphine, nicotine and phencyclidine(7-10). The sustained accumulation of Delta FosB in the nucleus accumbens indicates that this transcription factor may mediate some of the persistent neural and behavioural plasticity that accompanies chronic drug exposure(1). Using transgenic mice in which Delta FosB can be induced in adults in the subset of nucleus accumbens neurons in which cocaine induces the protein,we show that Delta FosB expression increases the responsiveness of an animal to the rewarding and locomotor-activating effects of cocaine. These effects of Delta FosB appear to be mediated partly by induction of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole) glutamate receptor subunit GluR2 in the nucleus accumbens. These results support a model in which Delta FosB, by altering gene expression, enhances sensitivity to cocaine and may thereby contribute to cocaine addiction.
    BibTeX:
    @article{Kelz1999,
      author = {Kelz, MB and Chen, JS and Carlezon, WA and Whisler, K and Gilden, L and Beckmann, AM and Steffen, C and Zhang, YJ and Marotti, L and Self, DW and Tkatch, T and Baranauskas, G and Surmeier, DJ and Neve, RL and Duman, RS and Picciotto, MR and Nestler, EJ},
      title = {Expression of the transcription factor Delta FosB in the brain controls sensitivity to cocaine},
      journal = {NATURE},
      year = {1999},
      volume = {401},
      number = {6750},
      pages = {272-276}
    }
    
    Kilts, C., Schweitzer, J., Quinn, C., Gross, R., Faber, T., Muhammad, F., Ely, T., Hoffman, J. & Drexler, K. Neural activity related to drug craving in cocaine addiction {2001} ARCHIVES OF GENERAL PSYCHIATRY
    Vol. {58}({4}), pp. {334-341} 
    article  
    Abstract: Background: Crack cocaine dependence and addiction is typically associated with frequent and intense drug wanting or craving triggered by internal or environmental cues associated with past drug use. Methods: Water O 15 positron emission tomography (PET) studies were used to localize alterations in synaptic activity related to cue-induced drug craving in 8 crack cocaine-dependent African American men. In a novel approach, script-guided imagery of autobiographical memories were used as individualized cues to internally generate a cocaine craving state and 2 control (ie, anger and neutral episodic memory recall) states during PET image acquisition. Results: The mental imagery of personalized drug use and anger-related scripts was associated with self-ratings of robust drug craving or anger, and comparable alterations in heart rate. Compared with the neutral imagery control condition, imagery-induced drug craving was associated with bilateral (right hemisphere amygdala activation greater than left) activation of the amygdala, the left insula and anterior cingulate gyrus, and the right subcallosal gyrus and nucleus accumbens area. Compared with the anger control condition, internally generated drug craving was associated with bilateral activation of the insula and subcallosal cortex, left hippocampus, and anterior cingulate cortex and brainstem. A brain-wide pixel-by-pixel search indicated significant positive and negative correlations between imagery-induced cocaine craving and regional cerebral blood flow (rCBF) in distributed sites. Conclusions: The collected findings suggest the craving-related activation of a network of limbic, paralimbic, and striatal brain regions, including structures involved in stimulus-reward association (amygdala), incentive motivation (subcallosal gyrus/nucleus accumbens), and anticipation (anterior cingulate cortex).
    BibTeX:
    @article{Kilts2001,
      author = {Kilts, CD and Schweitzer, JB and Quinn, CK and Gross, RE and Faber, TL and Muhammad, F and Ely, TD and Hoffman, JM and Drexler, KPG},
      title = {Neural activity related to drug craving in cocaine addiction},
      journal = {ARCHIVES OF GENERAL PSYCHIATRY},
      year = {2001},
      volume = {58},
      number = {4},
      pages = {334-341}
    }
    
    Kinon, B. & Lieberman, J. Mechanisms of action of atypical antipsychotic drugs: A critical analysis {1996} PSYCHOPHARMACOLOGY
    Vol. {124}({1-2}), pp. {2-34} 
    article  
    Abstract: Various criteria used to define atypical antipsychotic drugs include: 1) decrease, or absence, of the capacity to cause acute extrapyramidal motor side effects (acute EPSE) and tardive dyskinesia (TD); 2) increased therapeutic efficacy reflected by improvement in positive, negative, or cognitive symptoms; 3) and a decrease, or absence. of the capacity to increase prolactin levels. The pharmacologic basis of atypical antipsychotic drug activity has been the target of intensive study since the significance of clozapine was first appreciated. Three notions have been utilized conceptually to explain the distinction between atypical versus typical antipsychotic drugs: 1) dose-response separation between particular pharmacologic functions; 2) anatomic specificity of particular pharmacologic activities; 3) neurotransmitter receptor interactions and pharmacodynamics. These conceptual bases are not mutually exclusive, and the demonstration of limbic versus extrapyramidal motor functional selectivity is apparent within each arbitrary theoretical base. This review discusses salient distinctions predominantly between prototypic atypical and typical antipsychotic drugs such as clozapine and haloperidol, respectively. In addition, areas of common function between atypical and typical antipsychotic drug action may also be crucial to our identification of pathophysiological foci of the different dimensions of schizophrenia, including positive symptoms, negative symptoms, and neurocognitive deficits.
    BibTeX:
    @article{Kinon1996,
      author = {Kinon, BJ and Lieberman, JA},
      title = {Mechanisms of action of atypical antipsychotic drugs: A critical analysis},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1996},
      volume = {124},
      number = {1-2},
      pages = {2-34}
    }
    
    Kirkham, T., Williams, C., Fezza, F. & Di Marzo, V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol {2002} BRITISH JOURNAL OF PHARMACOLOGY
    Vol. {136}({4}), pp. {550-557} 
    article  
    Abstract: 1 Endocarinabinoids are implicated in appetite and body weight regulation. In rodents, anandamide stimulates eating by actions at central CB1 receptors, and hypothalamic endocannabinoids may be under the negative control of leptin. However, changes to brain endocannabinoid levels in direct relation to feeding or changing nutritional status have not been investigated. 2 We measured anandamide and 2-arachidonoyl glycerol (2-AG) levels in feeding-associated brain regions of rats, during fasting, feeding of a palatable food, or after satiation. Endocannabinoid levels were compared to those in rats fed ad libitum, at a point in their daily cycle when motivation to cat was absent. Fasting increased levels of anandamide and 2-AG in the limbic forebrain and, to a lesser extent, of 2-AG in the hypothalamus. By contrast, hypothalamic 2-AG declined as animals ate. No changes were detected in satiated rats, Endocannabinoid levels in the cerebellum, a control region not directly involved in the control of food intake, were unaffected by any manipulation. 3 As 2-AG was most sensitive to variation during feeding, and to leptin regulation in a previous study, we examined the behavioural effects of 2-AG when injected into the nucleus accumbens shell, a limbic forebrain area strongly linked to eating motivation. 2-AG potently, and dose-dependently, stimulated feeding. This effect was attenuated by the CBI receptor antagonist SR141716. 4 These findings provide the first direct evidence of altered brain levels of endocannabinoids, and of 2-AG in particular, during fasting and feeding. The nature of these effects supports a role for endocannabinoids in the control of appetitive motivation.
    BibTeX:
    @article{Kirkham2002,
      author = {Kirkham, TC and Williams, CM and Fezza, F and Di Marzo, V},
      title = {Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol},
      journal = {BRITISH JOURNAL OF PHARMACOLOGY},
      year = {2002},
      volume = {136},
      number = {4},
      pages = {550-557}
    }
    
    KLITENICK, M., DEWITTE, P. & KALIVAS, P. REGULATION OF SOMATODENDRITIC DOPAMINE RELEASE IN THE VENTRAL TEGMENTAL AREA BY OPIOIDS AND GABA - AN INVIVO MICRODIALYSIS STUDY {1992} JOURNAL OF NEUROSCIENCE
    Vol. {12}({7}), pp. {2623-2632} 
    article  
    Abstract: Microdialysis of the ventral tegmental area in conscious rats was used to evaluate the influence of opioids and GABA agonists on extracellular levels of GABA and somatodendritically released dopamine. The administration of morphine through the dialysis probe elicited significant, dose-dependent increases in the levels of extracellular dopamine and significantly reduced the extracellular concentration of GABA. In contrast, a dose-dependent decrease in somatodendritic extracellular dopamine was produced following the administration of the GABA(B) agonist baclofen. The increase in dopamine levels elicited by morphine (100-mu-M) was completely blocked by either baclofen (100-mu-M) coadministration or peripheral injection of naloxone (2 mg/kg, i.p.). Application of the GABA(A) agonist muscimol produced a significant increase in both extracellular levels of dopamine and locomotor activity. The present results, together with other electrophysiological, neurochemical, and behavioral data, support a hypothesis that stimulation of mu-opioid or GABA(A) receptors inhibits the activity of GABAergic afferents to dopamine neurons, thereby removing tonic inhibitory regulation, whereas stimulation of GABA(B) receptors directly inhibits dopamine neurons.
    BibTeX:
    @article{KLITENICK1992,
      author = {KLITENICK, MA and DEWITTE, P and KALIVAS, PW},
      title = {REGULATION OF SOMATODENDRITIC DOPAMINE RELEASE IN THE VENTRAL TEGMENTAL AREA BY OPIOIDS AND GABA - AN INVIVO MICRODIALYSIS STUDY},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1992},
      volume = {12},
      number = {7},
      pages = {2623-2632}
    }
    
    Knutson, B., Adams, C., Fong, G. & Hommer, D. Anticipation of increasing monetary reward selectively recruits nucleus accumbens {2001} JOURNAL OF NEUROSCIENCE
    Vol. {21}({16}), pp. {art. no.-RC159} 
    article  
    Abstract: Comparative studies have implicated the nucleus accumbens (NAcc) in the anticipation of incentives, but the relative responsiveness of this neural substrate during anticipation of rewards versus punishments remains unclear. Using event-related functional magnetic resonance imaging, we investigated whether the anticipation of increasing monetary rewards and punishments would increase NAcc blood oxygen level-dependent contrast (hereafter, ``activation'') in eight healthy volunteers. Whereas anticipation of increasing rewards elicited both increasing self-reported happiness and NAcc activation, anticipation of increasing punishment elicited neither. However, anticipation of both rewards and punishments activated a different striatal region (the medial caudate). At the highest reward level (5.00), NAcc activation was correlated with individual differences in self-reported happiness elicited by the reward cues. These findings suggest that whereas other striatal areas may code for expected incentive magnitude, a region in the NAcc codes for expected positive incentive value.
    BibTeX:
    @article{Knutson2001a,
      author = {Knutson, B and Adams, CM and Fong, GW and Hommer, D},
      title = {Anticipation of increasing monetary reward selectively recruits nucleus accumbens},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2001},
      volume = {21},
      number = {16},
      pages = {art. no.-RC159}
    }
    
    Knutson, B., Fong, G., Adams, C., Varner, J. & Hommer, D. Dissociation of reward anticipation and outcome with event-related fMRI {2001} NEUROREPORT
    Vol. {12}({17}), pp. {3683-3687} 
    article  
    Abstract: Reward processing involves both appetitive and consummatory phases. We sought to examine whether reward anticipation vs outcomes would recruit different regions of ventral forebrain circuitry using event-related fMRI. Nine healthy volunteers participated in a monetary incentive delays task in which they either responded to a cued target for monetary reward, responded to a cued target for no reward, or did not respond to a cued target during scanning. Multiple regression analyses indicated that while anticipation of reward Ys non-reward activated foci in the ventral striatum, reward vs non-reward outcomes activated foci in the ventromedial frontal cortex. These findings suggest that reward anticipation band outcomes may differentially recruit distinct regions that lie along the trajectory of ascending dopamine projections. NeuroReport 12:3683-3687 (C) 2001 Lippincott Williams & Wilkins.
    BibTeX:
    @article{Knutson2001,
      author = {Knutson, B and Fong, GW and Adams, CM and Varner, JL and Hommer, D},
      title = {Dissociation of reward anticipation and outcome with event-related fMRI},
      journal = {NEUROREPORT},
      year = {2001},
      volume = {12},
      number = {17},
      pages = {3683-3687}
    }
    
    Knutson, B., Fong, G., Bennett, S., Adams, C. & Homme, D. A region of mesial prefrontal cortex tracks monetarily rewarding outcomes: characterization with rapid event-related fMRI {2003} NEUROIMAGE
    Vol. {18}({2}), pp. {263-272} 
    article DOI  
    Abstract: The function of the mesial prefrontal cortex (MPFC: including Brodman areas 10/12/32) remains an enigma. Current theories suggest a role in representing internal information, including emotional introspection, autonomic control, and a ``default state'' of semantic processing. Recent evidence also suggests that parts of this region may also play a role in processing reward outcomes. In this study, we investigated the possibility that a region of the MPFC would be preferentially recruited by monetary reward outcomes using a parametric monetary incentive delay (MID) task. Twelve healthy volunteers participated in functional magnetic resonance scans while playing the MID task. Group analyses indicated that while the ventral striatum was recruited by anticipation of monetary reward, a region of the MPFC, instead responded to rewarding monetary outcomes. Specifically, volume-of-interest analyses indicated that when volunteers received 5.00 after anticipating a 5.00 win, MPFC activity increased, whereas when volunteers did not receive 5.00 after anticipating a 5.00 win, MPFC activity decreased, relative to outcomes with no incentive value. These findings suggest that in the context of processing monetary rewards, a region of the MPFC preferentially tracks rewarding outcomes. (C) 2003 Elsevier Science (USA). All rights reserved.
    BibTeX:
    @article{Knutson2003,
      author = {Knutson, B and Fong, GW and Bennett, SM and Adams, CM and Homme, D},
      title = {A region of mesial prefrontal cortex tracks monetarily rewarding outcomes: characterization with rapid event-related fMRI},
      journal = {NEUROIMAGE},
      year = {2003},
      volume = {18},
      number = {2},
      pages = {263-272},
      doi = {{10.1016/S1053-8119(02)00057-5}}
    }
    
    Knutson, B., Taylor, J., Kaufman, M., Peterson, R. & Glover, G. Distributed neural representation of expected value {2005} JOURNAL OF NEUROSCIENCE
    Vol. {25}({19}), pp. {4806-4812} 
    article DOI  
    Abstract: Anticipated reward magnitude and probability comprise dual components of expected value ( EV), a cornerstone of economic and psychological theory. However, the neural mechanisms that compute EV have not been characterized. Using event- related functional magnetic resonance imaging, we examined neural activation as subjects anticipated monetary gains and losses that varied in magnitude and probability. Group analyses indicated that, although the subcortical nucleus accumbens ( NAcc) activated proportional to anticipated gain magnitude, the cortical mesial prefrontal cortex ( MPFC) additionally activated according to anticipated gain probability. Individual difference analyses indicated that, although NAcc activation correlated with self- reported positive arousal, MPFC activation correlated with probability estimates. These findings suggest that mesolimbic brain regions support the computation of EV in an ascending and distributed manner: whereas subcortical regions represent an affective component, cortical regions also represent a probabilistic component, and, furthermore, may integrate the two.
    BibTeX:
    @article{Knutson2005,
      author = {Knutson, B and Taylor, J and Kaufman, M and Peterson, R and Glover, G},
      title = {Distributed neural representation of expected value},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2005},
      volume = {25},
      number = {19},
      pages = {4806-4812},
      doi = {{10.1523/JNEUROSCI.0642-05.2005}}
    }
    
    Knutson, B., Westdorp, A., Kaiser, E. & Hommer, D. FMRI visualization of brain activity during a monetary incentive delay task {2000} NEUROIMAGE
    Vol. {12}({1}), pp. {20-27} 
    article  
    Abstract: Comparative studies have implicated striatal and mesial forebrain circuitry in the generation of autonomic, endocrine, and behavioral responses for incentives. Using blood oxygen level-dependent functional magnetic resonance imaging, we sought to visualize functional activation of these regions in 12 normal volunteers as they anticipated and responded for monetary incentives. Both individual and group analyses of time-series data revealed significant activation of striatal and mesial forebrain structures (including insula, caudate, putamen, and mesial prefrontal cortex) during trials involving both monetary rewards and punishments. In addition to these areas, during trials involving punishment, group analysis revealed activation foci in the anterior cingulate and thalamus. These results corroborate comparative studies which implicate striatal and mesial forebrain circuitry in the elaboration of incentive-driven behavior. This report also introduces a new paradigm for probing the functional integrity of this circuitry in humans.
    BibTeX:
    @article{Knutson2000,
      author = {Knutson, B and Westdorp, A and Kaiser, E and Hommer, D},
      title = {FMRI visualization of brain activity during a monetary incentive delay task},
      journal = {NEUROIMAGE},
      year = {2000},
      volume = {12},
      number = {1},
      pages = {20-27}
    }
    
    KONRADI, C., COLE, R., HECKERS, S. & HYMAN, S. AMPHETAMINE REGULATES GENE-EXPRESSION IN RAT STRIATUM VIA TRANSCRIPTION FACTOR CREB {1994} JOURNAL OF NEUROSCIENCE
    Vol. {14}({9}), pp. {5623-5634} 
    article  
    Abstract: Amphetamine is a psychostimulant drug of abuse that can produce long-lived changes in behavior including sensitization and dependence. The neural substrates of these drug effects remain unknown, but based on their prolonged time course, we hypothesize that they involve drug-induced alterations in gene expression. It has recently been demonstrated that amphetamine regulates the expression of several genes, including c-fos, via dopamine D1 receptors in rat striatum. Here we report that amphetamine induces phosphorylation of transcription factor cAMP response element binding protein (CREB) in rat striatum in vivo and that dopamine D1 receptor stimulation induces phosphorylation of CREB within specific complexes bound to cAMP regulatory elements. In addition, we show by antisense injection that CREB is necessary for c-fos induction by amphetamine in vivo. Since CREB has been implicated in the activation of a number of immediate-early genes as well as several neuropeptide genes, CREB phosphorylation may be an important early nuclear event mediating long-term consequences of amphetamine administration.
    BibTeX:
    @article{KONRADI1994,
      author = {KONRADI, C and COLE, RL and HECKERS, S and HYMAN, SE},
      title = {AMPHETAMINE REGULATES GENE-EXPRESSION IN RAT STRIATUM VIA TRANSCRIPTION FACTOR CREB},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1994},
      volume = {14},
      number = {9},
      pages = {5623-5634}
    }
    
    Koob, G. Alcoholism: Allostasis and beyond {2003} ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
    Vol. {27}({2}), pp. {232-243} 
    article DOI  
    Abstract: Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the,extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma-aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin-releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition.
    BibTeX:
    @article{Koob2003,
      author = {Koob, GF},
      title = {Alcoholism: Allostasis and beyond},
      journal = {ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH},
      year = {2003},
      volume = {27},
      number = {2},
      pages = {232-243},
      doi = {{10.1097/01.ALC.0000057122.36127.C2}}
    }
    
    KOOB, G. DRUGS OF ABUSE - ANATOMY, PHARMACOLOGY AND FUNCTION OF REWARD PATHWAYS {1992} TRENDS IN PHARMACOLOGICAL SCIENCES
    Vol. {13}({5}), pp. {177-184} 
    article  
    Abstract: Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward - dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABA(A) receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.
    BibTeX:
    @article{KOOB1992,
      author = {KOOB, GF},
      title = {DRUGS OF ABUSE - ANATOMY, PHARMACOLOGY AND FUNCTION OF REWARD PATHWAYS},
      journal = {TRENDS IN PHARMACOLOGICAL SCIENCES},
      year = {1992},
      volume = {13},
      number = {5},
      pages = {177-184}
    }
    
    KOOB, G. NEURAL MECHANISMS OF DRUG REINFORCEMENT {1992} ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
    Vol. {654}, pp. {171-191} 
    article  
    BibTeX:
    @article{KOOB1992a,
      author = {KOOB, GF},
      title = {NEURAL MECHANISMS OF DRUG REINFORCEMENT},
      journal = {ANNALS OF THE NEW YORK ACADEMY OF SCIENCES},
      year = {1992},
      volume = {654},
      pages = {171-191}
    }
    
    Koob, G. & LeMoal, M. Drug abuse: Hedonic homeostatic dysregulation {1997} SCIENCE
    Vol. {278}({5335}), pp. {52-58} 
    article  
    Abstract: Understanding the neurobiological mechanisms of addiction requires an integration of basic neuroscience with social psychology, experimental psychology, and psychiatry. Addition is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and a loss of control over drug-taking. Sensitization and counteradaptation are hypothesized to contribute to this hedonic homeostatic dysregulation, and the neurobiological mechanisms involved, such as the mesolimbic dopamine system, opioid peptidergic systems, and brain and hormonal stress systems, are beginning to be characterized. This framework provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and to relapse in individuals with a history of addiction.
    BibTeX:
    @article{Koob1997,
      author = {Koob, GF and LeMoal, M},
      title = {Drug abuse: Hedonic homeostatic dysregulation},
      journal = {SCIENCE},
      year = {1997},
      volume = {278},
      number = {5335},
      pages = {52-58}
    }
    
    KOOB, G., MALDONADO, R. & STINUS, L. NEURAL SUBSTRATES OF OPIATE WITHDRAWAL {1992} TRENDS IN NEUROSCIENCES
    Vol. {15}({5}), pp. {186-191} 
    article  
    Abstract: Drug withdrawal is an integral part of most types of dependence and, to a large extent, opiate withdrawal has been considered the prototypic, classic measure of opiate dependence. The opiate withdrawal syndrome is characterized by multiple behavioral and physiological signs such as behavioral activation, ptosis, diarrhea, `wet dog' shakes and motivational dysfunction, which may be represented in the CNS at multiple sites. It seems that the activating effects associated with the opiate withdrawal syndrome may be mediated IV the nucleus locus coeruleus. Other signs such as wet dog shakes may involve sites in the hypothalamus important for temperature regulation. Certain other signs such as diarrhea and lacrimation may be dependent on peripheral opiate receptors. The motivational aspects of opiate withdrawal as demonstrated by the aversive stimulus effects or negative reinforcing effects (e.g. disrupted lever-pressing for food and Place aversions) may involve those elements of the nucleus accumbens that are known to be important for the acute reinforcing effects of opiates in nondependent rats. Evidence exists at the cellular and molecular level for both `within-system' and `between-system' adaptations to dependence. Elucidation of the neural networks, cellular mechanisms and molecular elements involved in opiate withdrawal may Provide not only a model for our understanding of the adaptive Processes associated with drug dependence. but also of those associated with other chronic insults to CNS function.
    BibTeX:
    @article{KOOB1992b,
      author = {KOOB, GF and MALDONADO, R and STINUS, L},
      title = {NEURAL SUBSTRATES OF OPIATE WITHDRAWAL},
      journal = {TRENDS IN NEUROSCIENCES},
      year = {1992},
      volume = {15},
      number = {5},
      pages = {186-191}
    }
    
    Koob, G. & Nestler, E. The neurobiology of drug addiction {1997} JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES
    Vol. {9}({3}), pp. {482-497} 
    article  
    Abstract: Animal models have begun to provide insights into the neurobiological basis of reinforcement in drug addiction. The reinforcing effects of indirect sympathomimetics such as cocaine and amphetamine appear to depend on release of dopamine in the terminal fields of the mesocorticolimbic dopamine system. The acute reinforcing effects of opiates involve not only an activation of dopamine, but also dopamine-independent elements in the terminal regions of the mesocorticolimbic dopamine system. Nicotine's reinforcing effects may involve both dopaminergic and opioid peptidergic systems. Ethanol's reinforcing effects may result from multiple neurotransmitter interactions including gamma-aminobutyric acid, glutamate, dopamine, opioid peptides, and serotonin. Subtle changes in neurochemical function and signal transduction and transcription mechanisms in sensitive neuronal elements in the extended amygdala may be mediators of chronic drug action that lead to vulnerability to relapse and may provide exciting insight into the neuroadaptations associated with drug addiction.
    BibTeX:
    @article{Koob1997a,
      author = {Koob, GF and Nestler, EJ},
      title = {The neurobiology of drug addiction},
      journal = {JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES},
      year = {1997},
      volume = {9},
      number = {3},
      pages = {482-497}
    }
    
    KOOB, G., RILEY, S., SMITH, S. & ROBBINS, T. EFFECTS OF 6-HYDROXYDOPAMINE LESIONS OF NUCLEUS ACCUMBENS SEPTI AND OLFACTORY TUBERCLE ON FEEDING, LOCOMOTOR-ACTIVITY, AND AMPHETAMINE ANOREXIA IN RAT {1978} JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY
    Vol. {92}({5}), pp. {917-927} 
    article  
    BibTeX:
    @article{KOOB1978,
      author = {KOOB, GF and RILEY, SJ and SMITH, SC and ROBBINS, TW},
      title = {EFFECTS OF 6-HYDROXYDOPAMINE LESIONS OF NUCLEUS ACCUMBENS SEPTI AND OLFACTORY TUBERCLE ON FEEDING, LOCOMOTOR-ACTIVITY, AND AMPHETAMINE ANOREXIA IN RAT},
      journal = {JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY},
      year = {1978},
      volume = {92},
      number = {5},
      pages = {917-927}
    }
    
    Koob, G., Roberts, A., Schulteis, G., Parsons, L., Heyser, C., Hyytia, P., Merlo-Pich, E. & Weiss, F. Neurocircuitry targets in ethanol reward and dependence {1998} ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
    Vol. {22}({1}), pp. {3-9} 
    article  
    Abstract: Alcoholism is a complex behavioral disorder characterized by excessive consumption of ethanol, a narrowing of the behavioral repertoire toward excessive consumption, the development of tolerance and dependence, and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome. Recent work has begun to define the neurocircuits responsible for the two major sources of reinforcement key to animal models of excessive ethanol intake: positive and negative reinforcement. Ethanol appears to interact with ethanol-sensitive elements within neuronal membranes that convey the specificity of neurochemical action. Ethanol reinforcement appears to be mediated by an activation of GABA-A receptors, release of opioid peptides, release of dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic ethanol administration as reflected by opposite effects during acute ethanol withdrawal and by the recruitment of other neurotransmitter systems such as the stress neuropeptide corticotropin-releasing factor. Future challenges will include a focus on understanding how these neuroadaptive changes convey vulnerability to relapse in animals with a history of ethanol dependence.
    BibTeX:
    @article{Koob1998a,
      author = {Koob, GF and Roberts, AJ and Schulteis, G and Parsons, LH and Heyser, CJ and Hyytia, P and Merlo-Pich, E and Weiss, F},
      title = {Neurocircuitry targets in ethanol reward and dependence},
      journal = {ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH},
      year = {1998},
      volume = {22},
      number = {1},
      pages = {3-9},
      note = {Symposium on Approaches for Studying Neural Circuits - Application to Alcohol Research at the 26th Annual Meeting of the Society-for-Neuroscience, WASHINGTON, D.C., NOV 16, 1996}
    }
    
    Koob, G., Sanna, P. & Bloom, F. Neuroscience of addiction {1998} NEURON
    Vol. {21}({3}), pp. {467-476} 
    article  
    BibTeX:
    @article{Koob1998,
      author = {Koob, GF and Sanna, PP and Bloom, FE},
      title = {Neuroscience of addiction},
      journal = {NEURON},
      year = {1998},
      volume = {21},
      number = {3},
      pages = {467-476}
    }
    
    Koos, T. & Tepper, J. Inhibitory control of neostriatal projection neurons by GABAergic interneurons {1999} NATURE NEUROSCIENCE
    Vol. {2}({5}), pp. {467-472} 
    article  
    Abstract: The basal ganglia are a highly interconnected network of nuclei essential for the modulation and execution of voluntary behavior. The neostriatum is the principal input and one of the principal controllers of the output of the basal ganglia. Neostriatal projection neurons seem to be dynamically and powerfully controlled by GABAergic inputs, but the source(s) and physiological properties of these inputs remain unclear. Here we use paired whole-cell recordings to show that this inhibition derives from small populations of GABAergic interneurons that are themselves interconnected through functional electrotonic synapses. Inhibitory synaptic potentials generated from single interneurons are sufficiently powerful to delay or entirely block the generation of action potentials in a large number of projection neurons simultaneously.
    BibTeX:
    @article{Koos1999,
      author = {Koos, T and Tepper, JM},
      title = {Inhibitory control of neostriatal projection neurons by GABAergic interneurons},
      journal = {NATURE NEUROSCIENCE},
      year = {1999},
      volume = {2},
      number = {5},
      pages = {467-472}
    }
    
    Kostich, W., Chen, A., Sperle, K. & Largent, B. Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: The CRF2 gamma receptor {1998} MOLECULAR ENDOCRINOLOGY
    Vol. {12}({8}), pp. {1077-1085} 
    article  
    Abstract: We report the discovery of a new CRF2 receptor splice isoform found in human brain, which we have termed the CRF2 gamma receptor. The CRF2 gamma cDNA encodes for a 397-amino acid receptor that has an amino terminus with no significant homology to the already reported alpha- and beta-termini. When expressed in 293-EBNA (Epstein-Barr nuclear antigen) cells, the CRF,, receptor responds in a dose-dependent manner to CRF and related peptides with a rank order of potency of urocortin greater than or equal to sauvagine>urotensin>r/h CRF, with EC50 values more similar to CRF2 alpha than CRF2 beta. Equilibrium saturation isotherm analysis with radiolabeled sauvagine reveals a two site/state model for binding to CRF2 gamma with a 60 pM K-d high-affinity site and a 5 nM K-d low-affinity site. Analysis of CRF2 gamma RNA expression in human brain demonstrates expression in septum and hippocampus, with weaker but detectable expression in amygdala, nucleus accumbens, midbrain, and frontal cortex.
    BibTeX:
    @article{Kostich1998,
      author = {Kostich, WA and Chen, AR and Sperle, K and Largent, BL},
      title = {Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: The CRF2 gamma receptor},
      journal = {MOLECULAR ENDOCRINOLOGY},
      year = {1998},
      volume = {12},
      number = {8},
      pages = {1077-1085}
    }
    
    Koylu, E., Couceyro, P., Lambert, P. & Kuhar, M. Cocaine- and amphetamine-regulated transcript peptide immunohistochemical localization in the rat brain {1998} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {391}({1}), pp. {115-132} 
    article  
    Abstract: Cocaine- and amphetamine-regulated transcript (CART) is a brain-enriched mRNA with a protein product(s) that is a candidate brain neurotransmitter. We have developed antisera to CART peptide fragment 106-129 and have demonstrated specific immunoreactivity (IR) at the light microscopic level throughout the brain, spinal cord, and retina. All brain nuclei previously shown to express CART mRNA are now shown to contain CART peptide IR. Although it is premature to define CART peptide(s) as a neurotransmitter(s), the localization found here suggests an involvement of CART in many processes. CART peptide staining in the nucleus accumbens and basolateral amygdala continue to suggest a role in drug-induced reward and reinforcement. Staining in the olfactory bulbs, the cortical barrels, the retina and its projection areas, the thalamic nuclei, the lateral and dorsal horns of the spinal cord, and the nuclei of the solitary tract are compatible with a major role for CART in sensory processing and autonomic regulation. CART peptides appear to colocalize with some classical neurotransmitters and appear to occur in peripheral neurons as well. (C) 1998 Wiley-Liss, Inc.
    BibTeX:
    @article{Koylu1998,
      author = {Koylu, EO and Couceyro, PR and Lambert, PD and Kuhar, MJ},
      title = {Cocaine- and amphetamine-regulated transcript peptide immunohistochemical localization in the rat brain},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1998},
      volume = {391},
      number = {1},
      pages = {115-132}
    }
    
    Kreek, M. & Koob, G. Drug dependence: stress and dysregulation of brain reward pathways {1998} DRUG AND ALCOHOL DEPENDENCE
    Vol. {51}({1-2}), pp. {23-47} 
    article  
    BibTeX:
    @article{Kreek1998,
      author = {Kreek, MJ and Koob, GF},
      title = {Drug dependence: stress and dysregulation of brain reward pathways},
      journal = {DRUG AND ALCOHOL DEPENDENCE},
      year = {1998},
      volume = {51},
      number = {1-2},
      pages = {23-47}
    }
    
    Kuczenski, R. & Segal, D. Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine {1997} JOURNAL OF NEUROCHEMISTRY
    Vol. {68}({5}), pp. {2032-2037} 
    article  
    Abstract: Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.
    BibTeX:
    @article{Kuczenski1997,
      author = {Kuczenski, R and Segal, DS},
      title = {Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1997},
      volume = {68},
      number = {5},
      pages = {2032-2037}
    }
    
    KUCZENSKI, R., SEGAL, D. & AIZENSTEIN, M. AMPHETAMINE, COCAINE, AND FENCAMFAMINE - RELATIONSHIP BETWEEN LOCOMOTOR AND STEREOTYPY RESPONSE PROFILES AND CAUDATE AND ACCUMBENS-DOPAMINE DYNAMICS {1991} JOURNAL OF NEUROSCIENCE
    Vol. {11}({9}), pp. {2703-2712} 
    article  
    Abstract: Using in vivo microdialysis, the caudate and nucleus accumbens dopamine (DA) responses to the psychomotor stimulants amphetamine (AMPH), cocaine (COC), and fencamfamine (FCF) were evaluated in rats concurrent with characterization of their behavioral response profiles. Doses of each stimulant that produced either enhanced locomotion or a prolonged period of intense focused stereotypies were examined to evaluate the quantitative relationships between stimulant-induced behaviors and changes in DA dynamics and to test the hypothesis that a balance between mesostriatal and mesolimbic DA activity contributes to the appearance of specific stimulant-induced behaviors. Although 10 mg/kg COC and 1.7 mg/kg FCF promoted levels of locomotor activity substantially greater than 0.5 mg/kg AMPH, the magnitude of the DA increases in both caudate and accumbens were markedly less than was obtained following AMPH. Thus, stimulant-induced locomotion appears to be dissociated from the quantitative DA response in both brain regions. This behavioral/DA dissociation was also apparent at higher doses of AMPH (2.5 mg/kg), COC (40 mg/kg), and FCF (6 mg/kg), doses that promoted a behavioral pattern that included a prolonged period of intense stereotypy. Indeed, the regional DA responses to these high doses of COC and FCF were substantially less than the response to 0.5 mg/kg AMPH. Furthermore, there were no differences in the ratio of the caudate and accumbens DA responses as a function of dose for any of the three drugs. Thus, the balance between the regional DA activation does not appear to regulate the expression of the behavioral response. Additionally, the effects of these stimulants on regional DA metabolite concentrations were compared. The results indicate that AMPH promoted an identical pattern of effects on caudate and accumbens DA metabolites, suggesting that similar mechanisms govern the dynamics of DA in response to AMPH in both brain regions. In contrast, the DA uptake blockers promoted some region-specific effects on DA metabolites that may be due to regional differences in the DA metabolism and rates of impulse flow.
    BibTeX:
    @article{KUCZENSKI1991,
      author = {KUCZENSKI, R and SEGAL, DS and AIZENSTEIN, ML},
      title = {AMPHETAMINE, COCAINE, AND FENCAMFAMINE - RELATIONSHIP BETWEEN LOCOMOTOR AND STEREOTYPY RESPONSE PROFILES AND CAUDATE AND ACCUMBENS-DOPAMINE DYNAMICS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1991},
      volume = {11},
      number = {9},
      pages = {2703-2712}
    }
    
    KUHAR, M., RITZ, M. & BOJA, J. THE DOPAMINE HYPOTHESIS OF THE REINFORCING PROPERTIES OF COCAINE {1991} TRENDS IN NEUROSCIENCES
    Vol. {14}({7}), pp. {299-302} 
    article  
    Abstract: A variety of evidence suggests a `dopamine hypothesis' for the reinforcing properties of cocaine. This hypothesis proposes that cocaine binds at the dopamine transporter and mainly inhibits neurotransmitter re-uptake; the resulting potentiation of dopaminergic neurotransmission in mesolimbocortical pathways ultimately causes reinforcement. This model suggests potential medications for treatment of cocaine abuse and dependence. Some, but not all, pharmacological data in humans support the hypothesis and additional experimentation is needed.
    BibTeX:
    @article{KUHAR1991,
      author = {KUHAR, MJ and RITZ, MC and BOJA, JW},
      title = {THE DOPAMINE HYPOTHESIS OF THE REINFORCING PROPERTIES OF COCAINE},
      journal = {TRENDS IN NEUROSCIENCES},
      year = {1991},
      volume = {14},
      number = {7},
      pages = {299-302}
    }
    
    Kumar, A., Choi, K., Renthal, W., Tsankova, N., Theobald, D., Truong, H., Russo, S., LaPlant, Q., Sasaki, T., Whistler, K., Neve, R., Self, D. & Nestler, E. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum {2005} NEURON
    Vol. {48}({2}), pp. {303-314} 
    article DOI  
    Abstract: Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striaturn, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. Delta FosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.
    BibTeX:
    @article{Kumar2005,
      author = {Kumar, A and Choi, KH and Renthal, W and Tsankova, NM and Theobald, DEH and Truong, HT and Russo, SJ and LaPlant, Q and Sasaki, TS and Whistler, KN and Neve, RL and Self, DW and Nestler, EJ},
      title = {Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum},
      journal = {NEURON},
      year = {2005},
      volume = {48},
      number = {2},
      pages = {303-314},
      doi = {{10.1016/j.neuron.2005.09.023}}
    }
    
    Kuroki, T., Meltzer, H. & Ichikawa, J. Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens {1999} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {288}({2}), pp. {774-781} 
    article  
    Abstract: The present study was designed to compare the effects of typical and atypical antipsychotic drugs on extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis with dual probe implantation in awake, freely moving rats. Amperozide (2 and 10 mg/kg), clozapine (5 and 20 mg/kg), and olanzapine (10 mg/kg), all of which are atypical antipsychotics, produced greater increases in extracellular DA levels in the mPFC than in the NAG. Olanzapine (1 mg/kg), risperidone (0.1 and 1 mg/kg), also an atypical antipsychotic, and S-(-)-sulpiride (25 mg/kg), a typical antipsychotic, produced comparable increases in extracellular DA levels in the mPFC and the NAG. S-(-)-sulpiride (10 mg/kg) and haloperidol (0.1 and 1 mg/kg), another typical antipsychotic, significantly increased extracellular DA levels in the NAC but not in the mPFC. The effects of the six antipsychotic drugs to increase extracellular DA levels in the mPFC relative to those in the NAC was positively correlated with the difference between their pKi values for serotonin (5-hydroxytryptamine, 5-HT2A) and DA-D-2 receptors and was inversely correlated to their pKi values for D-2 or D-3 receptors, but was not for 5-HT2A receptors alone. These results are consistent with the hypothesis that the ability of antipsychotic drugs to produce a greater increase in prefrontal compared with NAC extracellular DA levels may be related, in part, to weak D-2 and D-3 receptor affinity relative to 5-HT2A receptor antagonism.
    BibTeX:
    @article{Kuroki1999,
      author = {Kuroki, T and Meltzer, HY and Ichikawa, J},
      title = {Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1999},
      volume = {288},
      number = {2},
      pages = {774-781},
      note = {25th Annual Meeting of the Society-for-Neuroscience, SAN DIEGO, CALIFORNIA, NOV 11-16, 1995}
    }
    
    LaneLadd, S., Pineda, J., Boundy, V., Pfeuffer, T., Krupinski, J., Aghajanian, G. & Nestler, E. CREB (cAMP response element-binding protein) in the locus coeruleus: Biochemical, physiological, and behavioral evidence for a role in opiate dependence {1997} JOURNAL OF NEUROSCIENCE
    Vol. {17}({20}), pp. {7890-7901} 
    article  
    Abstract: Chronic morphine administration increases levels of adenylyl cyclase and cAMP-dependent protein kinase (PKA) activity in the locus coeruleus (LC), which contributes to the severalfold activation of LC neurons that occurs during opiate withdrawal. A role for the transcription factor cAMP response element-binding protein (CREB) in mediating the opiate-induced upregulation of the cAMP pathway has been suggested, but direct evidence is lacking. In the present study, we first demonstrated that the morphine-induced increases in adenylyl cyclase and PKA activity in the LC are associated with selective increases in levels of immunoreactivity of types I and VIII adenylyl cyclase and of the catalytic and type II regulatory subunits of PKA. We next used antisense oligonucleotides directed against CREB to study the role of this transcription factor in mediating these effects. Infusion (5 d) of CREB antisense oligonucleotide directly into the LC significantly reduced levels of CREB immunoreactivity. This effect was sequence-specific and not associated with detectable toxicity. CREB antisense oligonucleotide infusions completely blocked the morphine-induced upregulation of type VIII adenylyl cyclase but not of PKA. The infusions also blocked the morphine-induced upregulation of tyrosine hydroxylase but not of Gi alpha, two other proteins induced in the LC by chronic morphine treatment. Electrophysiological studies revealed that intra-LC antisense oligonucleotide infusions completely prevented the morphine-induced increase in spontaneous firing rates of LC neurons in brain slices. This blockade was completely reversed by addition of 8-bromo-cAMP (which activates PKA) but not by addition of forskolin (which activates adenylyl cyclase). Intra-LC infusions of CREB antisense oligonucleotide also reduced the development of physical dependence to opiates, based on attenuation of opiate withdrawal. Together, these findings provide the first direct evidence that CREB mediates the morphine-induced upregulation of specific components of the cAMP pathway in the LC that contribute to physical opiate dependence.
    BibTeX:
    @article{LaneLadd1997,
      author = {LaneLadd, SB and Pineda, J and Boundy, VA and Pfeuffer, T and Krupinski, J and Aghajanian, GK and Nestler, EJ},
      title = {CREB (cAMP response element-binding protein) in the locus coeruleus: Biochemical, physiological, and behavioral evidence for a role in opiate dependence},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1997},
      volume = {17},
      number = {20},
      pages = {7890-7901}
    }
    
    LAPPER, S. & BOLAM, J. INPUT FROM THE FRONTAL-CORTEX AND THE PARAFASCICULAR NUCLEUS TO CHOLINERGIC INTERNEURONS IN THE DORSAL STRIATUM OF THE RAT {1992} NEUROSCIENCE
    Vol. {51}({3}), pp. {533-545} 
    article  
    Abstract: Evidence derived from many experimental approaches indicates that cholinergic neurons in the dorsal striatum (caudate-putamen) are responsive to excitatory amino acids. Furthermore, evidence from physiological experiments indicate that the excitatory input is derived from the cortex and/or the thalamus. The object of the present experiment was to anatomically test whether cholinergic neurons receive cortical and/or thalamic input in the dorsal striatum using a combined anterograde tracing and immunocytochemical approach at both the light- and electron-microscopic levels. Rats received injections of the anterograde tracers Phaseolus vulgaris-leucoagglutinin or biocytin at multipie sites in the frontal cortex or parafascicular nucleus of the thalamus. Sections of the striatum were stained to reveal the anterogradely transported markers and then immunostained to reveal choline acetyltransferase immunoreactivity. The striata of these animals contained dense networks of anterogradely labelled fibres that were dispersed throughout the neuropil and interspersed with the choline acetyltransferase-immunoreactive (i.e. cholinergic) perikarya and dendrites. The anterogradely labelled fibres were often closely apposed to the choline acetyltransferase-immunoreactive neurons. Examination of electron-microscopic sections failed to demonstrate cortical terminals in synaptic contact with the cholinergic neurons even when choline acetyltransferase-immunoreactive structures were examined that had first been identified in the light microscope as having cortical terminals closely apposed to them. In these cases it was often observed that the cortical terminal, although apposed to the membrane of the labelled neurone, made synaptic contact with an unlabelled spine that was in the vicinity. In contrast to the cortical input, analysis of material that was double-stained to reveal thalamostriatal terminals and choline acetyltransferase-immunoreactive structures, revealed that the thalamostriatal terminals were often in asymmetrical synaptic contact with the perikarya and dendrites of cholinergic neurons. It is concluded that the cholinergic neurons of the dorsal striatum, like those of the ventral striatum or nucleus accumbens [Meredith and Wouterlood (1990) J. comp. Neurol. 296, 204-221] receive very little or no input from the cortex but are under a prominent synaptic control by the thalamostriatal system. Those pharmacological effects of excitatory amino acids on the cholinergic systems of the striatum are therefore presumably related to the thalamostriatal and not the corticostriatal system.
    BibTeX:
    @article{LAPPER1992,
      author = {LAPPER, SR and BOLAM, JP},
      title = {INPUT FROM THE FRONTAL-CORTEX AND THE PARAFASCICULAR NUCLEUS TO CHOLINERGIC INTERNEURONS IN THE DORSAL STRIATUM OF THE RAT},
      journal = {NEUROSCIENCE},
      year = {1992},
      volume = {51},
      number = {3},
      pages = {533-545}
    }
    
    Laruelle, M., Abi-Dargham, A., Gil, R., Kegeles, L. & Innis, R. Increased dopamine transmission in schizophrenia: Relationship to illness phases {1999} BIOLOGICAL PSYCHIATRY
    Vol. {46}({1}), pp. {56-72} 
    article  
    Abstract: Background: Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyerdopaminergic stare in schizophrenia has been difficult to demonstrate, given the difficulty to measure dopamine transmission in the living human brain, Such evidence has recently emerged. Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared to matched healthy control subjects, thus demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a large variance was observed within the schizophrenic group in the magnitude of this finding, and clinical predictors of this effect could nor be identified. Methods: In this paper, we combined previously published and newly acquired data to obtain sufficient power to address this question. Results: The most important findings derived from this extended data set are: 1) dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications; 2) this dysregulation was observed in patients experiencing an episode of illness exacerbation, but not in patients studied during a remission phase. Conclusions: A hyperdopaminergic state is present in schizophrenia during the initial episode and subsequent relapses, but not in periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase. (C) 1999 Society of Biological Psychiatry.
    BibTeX:
    @article{Laruelle1999,
      author = {Laruelle, M and Abi-Dargham, A and Gil, R and Kegeles, L and Innis, R},
      title = {Increased dopamine transmission in schizophrenia: Relationship to illness phases},
      journal = {BIOLOGICAL PSYCHIATRY},
      year = {1999},
      volume = {46},
      number = {1},
      pages = {56-72},
      note = {Conference on Schizophrenia - From Molecule to Public Policy, SANTA FE, NEW MEXICO, OCT, 1998}
    }
    
    LEMOAL, M. & SIMON, H. MESOCORTICOLIMBIC DOPAMINERGIC NETWORK - FUNCTIONAL AND REGULATORY ROLES {1991} PHYSIOLOGICAL REVIEWS
    Vol. {71}({1}), pp. {155-234} 
    article  
    BibTeX:
    @article{LEMOAL1991,
      author = {LEMOAL, M and SIMON, H},
      title = {MESOCORTICOLIMBIC DOPAMINERGIC NETWORK - FUNCTIONAL AND REGULATORY ROLES},
      journal = {PHYSIOLOGICAL REVIEWS},
      year = {1991},
      volume = {71},
      number = {1},
      pages = {155-234}
    }
    
    LEMOINE, C. & BLOCH, B. D1 AND D2 DOPAMINE-RECEPTOR GENE-EXPRESSION IN THE RAT STRIATUM - SENSITIVE CRNA PROBES DEMONSTRATE PROMINENT SEGREGATION OF D1 AND D2 MESSENGER-RNAS IN DISTINCT NEURONAL POPULATIONS OF THE DORSAL AND VENTRAL STRIATUM {1995} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {355}({3}), pp. {418-426} 
    article  
    Abstract: The postsynaptic effects of dopamine in the striatum are mediated mainly by receptors encoded by D1, D2, and D3 dopamine receptor genes. The D1 and D2 genes are the most widely expressed in the caudate-putamen, the accumbens nucleus, and the olfactory tubercle. Several anatomical studies, including studies using in situ hybridization with oligonucleotide and cDNA probes, have suggested that D1 and D2 receptors are segregated into distinct efferent neuronal populations of the striatum: D1 in substance P striatonigral neurons and D2 in enkephalin striatopallidal neurons. In contrast, on the basis of several in vivo and in vitro studies, other authors have suggested the existence of an extensive colocalization of D1 and D2 in the same striatal neurons. Our study was undertaken in order to analyze in detail the expression of the D1 and D2 receptor genes in the efferent striatal populations, with special reference to the various striatal areas, and to yield insights into the question about D1 and D2 mRNA localization in the striatum. We have, therefore, used highly sensitive digoxigenin-and S-35-labeled cRNA probes to address this question. The present results demonstrate that the D1 and D2 receptor mRNAs are segregated, respectively, in substance P and enkephalin neurons in the caudate-putamen and accumbens nucleus (shell and core) and in the olfactory tubercle (for their largest part). A very small percentage of neurons may coexpress both genes. These results confirm that the D1 and D2 receptor genes are expressed in distinct populations of striatal efferent neurons in the normal adult rat. (C) 1995 Wiley-Liss, Inc.
    BibTeX:
    @article{LEMOINE1995,
      author = {LEMOINE, C and BLOCH, B},
      title = {D1 AND D2 DOPAMINE-RECEPTOR GENE-EXPRESSION IN THE RAT STRIATUM - SENSITIVE CRNA PROBES DEMONSTRATE PROMINENT SEGREGATION OF D1 AND D2 MESSENGER-RNAS IN DISTINCT NEURONAL POPULATIONS OF THE DORSAL AND VENTRAL STRIATUM},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1995},
      volume = {355},
      number = {3},
      pages = {418-426}
    }
    
    LEMOINE, C., NORMAND, E. & BLOCH, B. PHENOTYPICAL CHARACTERIZATION OF THE RAT STRIATAL NEURONS EXPRESSING THE D1 DOPAMINE RECEPTOR GENE {1991} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {88}({10}), pp. {4205-4209} 
    article  
    Abstract: In situ hybridization experiments were performed in rat brain sections from normal and 6-hydroxy-dopamine-treated rats in order to map and identify the neurons expressing the D1 receptor gene in the striatum and the substantia nigra. Procedures of combined in situ hybridization, allowing the simultaneous detection of two mRNAs in the same section or in adjacent sections, were used to characterize the phenotypes of the neurons expressing the D1 receptor gene. D1 receptor mRNA was found in neurons all over the caudate-putamen, the accumbens nucleus, and the olfactory tubercle but not in the substantia nigra. In the caudate-putamen and accumbens nucleus, most of the neurons containing D1 receptor mRNA were characterized as medium-sized substance P neurons and distinct from those containing D2 receptor mRNA. Nevertheless, 15-20% of the substance P neurons did not contain D1 receptor mRNA. The neurons containing preproenkephalin A mRNA did not contain D1 receptor mRNA but contained D2 receptor mRNA. A small number of cholinergic and somatostatinergic neurons exhibited a weak reaction for D1 receptor mRNA. These results demonstrate that dopamine acts on efferent striatal neurons through expression of distinct receptors - namely, D1 and D2 in separate cell populations (substance P and preproenkephalin A neurons, respectively) - and can also act on nonprojecting neurons through D1 receptor expression.
    BibTeX:
    @article{LEMOINE1991,
      author = {LEMOINE, C and NORMAND, E and BLOCH, B},
      title = {PHENOTYPICAL CHARACTERIZATION OF THE RAT STRIATAL NEURONS EXPRESSING THE D1 DOPAMINE RECEPTOR GENE},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1991},
      volume = {88},
      number = {10},
      pages = {4205-4209}
    }
    
    Levant, B. The D-3 dopamine receptor: Neurobiology and potential clinical relevance {1997} PHARMACOLOGICAL REVIEWS
    Vol. {49}({3}), pp. {231-252} 
    article  
    BibTeX:
    @article{Levant1997,
      author = {Levant, B},
      title = {The D-3 dopamine receptor: Neurobiology and potential clinical relevance},
      journal = {PHARMACOLOGICAL REVIEWS},
      year = {1997},
      volume = {49},
      number = {3},
      pages = {231-252}
    }
    
    LEVESQUE, D., DIAZ, J., PILON, C., MARTRES, M., GIROS, B., SOUIL, E., SCHOTT, D., MORGAT, J., SCHWARTZ, J. & SOKOLOFF, P. IDENTIFICATION, CHARACTERIZATION, AND LOCALIZATION OF THE DOPAMINE-D3 RECEPTOR IN RAT-BRAIN USING 7-[H-3]HYDROXY-N,N-DI-NORMAL-PROPYL-2-AMINOTETRALIN {1992} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {89}({17}), pp. {8155-8159} 
    article  
    Abstract: We have identified 7-[H-3]hydroxy-N,N-di-n-propyl-2-aminotetralin ([H-3]7-OH-DPAT) as a selective probe for the recently cloned dopamine D3 receptor and used it to assess the presence of this receptor and establish its distribution and properties in brain. In transfected Chinese hamster ovary (CHO) cells, it binds to D3 receptors with subnanomolar affinity, whereas its affinity is approximately 100-, 1000-, and 10,000-fold lower at D2, D4, and D1 receptors, respectively. Specific [H-3]7-OH-DPAT binding sites, with a K(d) of 0.8 nM and a pharmacology similar to those at reference D3 receptors of CHO cells, were identified in rat brain. D3 receptors differ from D2 receptors in brain by their lower abundance (2 orders of magnitude) and distribution, restricted to a few mainly phylogenetically ancient areas-e.g., paleostriatum and archicerebellum-as evidenced by membrane binding and autoradiography studies. Native D3 receptors in brain are characterized by an unusually high nanomolar affinity for dopamine and a low modulatory influence of guanyl nucleotides on agonist binding. These various features suggest that D3 receptors are involved in a peculiar mode of neurotransmission in a restricted subpopulation of dopamine neurons.
    BibTeX:
    @article{LEVESQUE1992,
      author = {LEVESQUE, D and DIAZ, J and PILON, C and MARTRES, MP and GIROS, B and SOUIL, E and SCHOTT, D and MORGAT, JL and SCHWARTZ, JC and SOKOLOFF, P},
      title = {IDENTIFICATION, CHARACTERIZATION, AND LOCALIZATION OF THE DOPAMINE-D3 RECEPTOR IN RAT-BRAIN USING 7-[H-3]HYDROXY-N,N-DI-NORMAL-PROPYL-2-AMINOTETRALIN},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1992},
      volume = {89},
      number = {17},
      pages = {8155-8159}
    }
    
    LEVIN, E. NICOTINIC SYSTEMS AND COGNITIVE FUNCTION {1992} PSYCHOPHARMACOLOGY
    Vol. {108}({4}), pp. {417-431} 
    article  
    Abstract: Nicotinic acetylcholine receptors have been found to be important for maintaining optimal performance on a variety of cognitive tasks. In humans, nicotine-induced improvement of rapid information processing is particularly well documented. In experimental animals nicotine has been found to improve learning and memory on a variety of tasks, while the nicotinic antagonist mecamylamine has been found to impair memory performance. Nicotine has been found to be effective in attenuating memory deficits resulting from lesions of the septohippocampal pathway or aging in experimental animals. Nicotinic receptors are decreased in the cortex of patients with Alzheimer's disease. Preliminary studies have found that some aspects of the cognitive deficit in Alzheimer's disease can be attenuated by nicotine. Nicotine may prove to be useful therapeutic treatment for this and other types of dementia.
    BibTeX:
    @article{LEVIN1992,
      author = {LEVIN, ED},
      title = {NICOTINIC SYSTEMS AND COGNITIVE FUNCTION},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1992},
      volume = {108},
      number = {4},
      pages = {417-431}
    }
    
    Liberzon, I., Taylor, S., Amdur, R., Jung, T., Chamberlain, K., Minoshima, S., Koeppe, R. & Fig, L. Brain activation in PTSD in response to trauma-related stimuli {1999} BIOLOGICAL PSYCHIATRY
    Vol. {45}({7}), pp. {817-826} 
    article  
    Abstract: Background: Repetitive recall of traumatic memories and chronic intermittent hyperarousal are characteristic of posttraumatic stress disorder (PTSD). Hyperarousal and memory dysfunction implicates ``limbic'' brain regions, including the amygdaloid complex, hippocampal formation, and limbic cortex, such as the orbitofrontal and anterior cingulate areas. To investigate the neurobiologic role of these brain regions in PTSD, we measured regional cerebral blood flow in PTSD with single photon emission computerized tomography (SPECT) during a symptom provocation paradigm. Methods: Fourteen Vietnam veterans with PTSD, 11 combat control subjects, and 14 normal control subjects were studied with [Tc-99m] HMPAO in two sessions 48 hours apart: one session after exposure to white noise and the other following exposure to combat sounds. Skin conductance, heart rate, and subjective experience were recorded at the time of the studies. Results: Activation for all three groups occurred in the anterior cingulate/middle prefrontal gyrus. Activation in the region of the left amygdala/nucleus accumbens was found in PTSD patients only. Deactivation was found in all three groups in the left retrosplenial region. Conclusions: These findings implicate regions of the ``limbic'' brain, which may mediate the response to aversive stimuli in healthy individuals and in patients suffering from PTSD. (C) 1999 Society of Biological Psychiatry.
    BibTeX:
    @article{Liberzon1999,
      author = {Liberzon, I and Taylor, SF and Amdur, R and Jung, TD and Chamberlain, KR and Minoshima, S and Koeppe, RA and Fig, LM},
      title = {Brain activation in PTSD in response to trauma-related stimuli},
      journal = {BIOLOGICAL PSYCHIATRY},
      year = {1999},
      volume = {45},
      number = {7},
      pages = {817-826}
    }
    
    LINDVALL, O., WIDNER, H., REHNCRONA, S., BRUNDIN, P., ODIN, P., GUSTAVII, B., FRACKOWIAK, R., LEENDERS, K., SAWLE, G., ROTHWELL, J., BJORKLUND, A. & MARSDEN, C. TRANSPLANTATION OF FETAL DOPAMINE NEURONS IN PARKINSONS-DISEASE - ONE-YEAR CLINICAL AND NEUROPHYSIOLOGICAL OBSERVATIONS IN 2 PATIENTS WITH PUTAMINAL IMPLANTS {1992} ANNALS OF NEUROLOGY
    Vol. {31}({2}), pp. {155-165} 
    article  
    Abstract: Ventral mesencephalic tissue from aborted human fetuses (age, 6-7 weeks' postconception) was implanted unilaterally into the putamen using stereotaxic surgery in 2 immunosuppressed patients (Patients 3 and 4 in our series) with advanced idiopathic Parkinson's disease. Tissue from 4 fetuses was grafted to each patient. Compared with our previous 2 patients, the following changes in the grafting procedure were introduced: the implantation instrument was thinner, more tissue was placed in the operated structure, and the time between abortion and grafting was shorter. There were no postoperative complications. Both patients showed a gradual and significant amelioration of parkinsonian symptoms (most marked in Patient 3) starting at 6 and 12 weeks after grafting, respectively, reaching maximum stability at approximately 4 to 5 months; patients remained relatively stable thereafter during the 1-year follow-up period. Clinical improvement was observed as a reduction of the time spent in the ``off `` phase and the number of daily ``off'' periods; a lessening of bradykinesia and rigidity during the ``off `` phase, mainly but not solely on the side contralateral to the graft; and a prolongation and change in the pattern of the effect of a single dose of L-dopa. Neurophysiological measurements revealed a more rapid performance of simple and complex arm and hand movements bilaterally, but primarily contralateral to the graft. The results indicate that patients with Parkinson's disease can show significant and sustained improvement of motor function after intrastriatal implantation of fetal dopamine-rich mesencephalic tissue. The accompanying paper by Sawle and colleagues describes the results of repeated positron emission tomography scans in these patients.
    BibTeX:
    @article{LINDVALL1992,
      author = {LINDVALL, O and WIDNER, H and REHNCRONA, S and BRUNDIN, P and ODIN, P and GUSTAVII, B and FRACKOWIAK, R and LEENDERS, KL and SAWLE, G and ROTHWELL, JC and BJORKLUND, A and MARSDEN, CD},
      title = {TRANSPLANTATION OF FETAL DOPAMINE NEURONS IN PARKINSONS-DISEASE - ONE-YEAR CLINICAL AND NEUROPHYSIOLOGICAL OBSERVATIONS IN 2 PATIENTS WITH PUTAMINAL IMPLANTS},
      journal = {ANNALS OF NEUROLOGY},
      year = {1992},
      volume = {31},
      number = {2},
      pages = {155-165}
    }
    
    LIPSKA, B., JASKIW, G. & WEINBERGER, D. POSTPUBERTAL EMERGENCE OF HYPERRESPONSIVENESS TO STRESS AND TO AMPHETAMINE AFTER NEONATAL EXCITOTOXIC HIPPOCAMPAL DAMAGE - A POTENTIAL ANIMAL-MODEL OF SCHIZOPHRENIA {1993} NEUROPSYCHOPHARMACOLOGY
    Vol. {9}({1}), pp. {67-75} 
    article  
    Abstract: The constellation of major phenomena associated with schizophrenia (e.g., postpubertal onset, congenital hippocampal area damage, cortical functional deficits, limbic dopamine (DA) dysregulation, and vulnerability to stress) have been difficult to explain with a unitary animal model. Although it has been shown that rats develop increased mesolimbic DA transmission and reduced cortical DA turnover following adult excitotoxic lesions of the ventral hippocampus (VH), the implication of early developmental VH lesions are not known. To determine the developmental sequelae of such changes, we produced ibotenic acid lesions of the ventral hippocampal formation in rats on the 7th day after birth (PD7). Motor activity in a novel environment, after saline injection and after d-amphetamine administration were similar in control and lesioned rats at PD35. However, in early adulthood, at PD56, animals with the hippocampal lesion were hyperactive in each of these conditions. The emergence of the hyperactivity at PD56 could be prevented by pretreatment with haloperidol. Moreover, rats lesioned as neonates, in contrast to a similar lesion induced in adult animals, were also hyperresponsive to stress evaluated with a swim test. This latter effect is analogous to that seen after adult lesions of the medial prefrontal cortex, rather than after adult lesions of VH, suggesting that the neonatal VH lesion may affect functional development of the medial prefrontal cortex. These results demonstrate that in rats with neonatally induced excitotoxic VH lesions, behavioral indices consistent with increased mesolimbic DA responsivity to stressful and to pharmacologic stimuli emerge only in early adulthood. Homologous mechanisms may underlie certain aspects of the pathophysiology of schizophrenia.
    BibTeX:
    @article{LIPSKA1993,
      author = {LIPSKA, BK and JASKIW, GE and WEINBERGER, DR},
      title = {POSTPUBERTAL EMERGENCE OF HYPERRESPONSIVENESS TO STRESS AND TO AMPHETAMINE AFTER NEONATAL EXCITOTOXIC HIPPOCAMPAL DAMAGE - A POTENTIAL ANIMAL-MODEL OF SCHIZOPHRENIA},
      journal = {NEUROPSYCHOPHARMACOLOGY},
      year = {1993},
      volume = {9},
      number = {1},
      pages = {67-75}
    }
    
    Lipska, B., Swerdlow, N., Geyer, M., Jaskiw, G., Braff, D. & Weinberger, D. Neonatal excitotoxic hippocampal damage in rats causes post pubertal changes in prepulse inhibition of startle and its disruption by apomorphine {1995} PSYCHOPHARMACOLOGY
    Vol. {122}({1}), pp. {35-43} 
    article  
    Abstract: Neonatal excitotoxic hippocampal damage in the rat results in postpubertal onset of a variety of abnormal behaviors related to excessive dopaminergic transmission in the mesolimbic/nigrostriatal system; and thus may be considered an animal model of some aspects of schizophrenia. Because sensorimotor gating is impaired in adult patients with schizophrenia and in rats with experimentally induced mesolimbic dopamine hyperactivity, the present experiments investigated the effects of neonatal (postnatal day 7, PD7) ibotenic acid (3 mu g) lesions of the ventral hippocampus (VH) on the amplitude and prepulse inhibition (PPI) of acoustic startle in prepubertal (PD35) and postpubertal (PD56) rats. Startle was elicited using 105 and 118-dB pulses alone or preceded by 4, 8, or 16 dB above-background prepulses in rats treated with vehicle or apomorphine (APO; 0.025 or 0.1 mg/kg SC). At PD35, PPI in VH-lesioned rats did not differ significantly from these measures in sham operated rats. Apomorphine significantly increased startle amplitude and reduced PPI in both sham operated and VH-lesioned rats at PD35. At PD56, startle amplitude in VH-lesioned rats was not significantly different from controls, but PPI was reduced significantly compared to controls. Ventral hippocampus lesioned rats also exhibited an exaggerated reduction in PPI after treatment with APO. These findings provide further evidence of postpubertal impairments that may be related to increased mesolimbic dopamine transmission and receptor sensitivity in rats with neonatal hippocampal damage. and provide further support for the fidelity of this animal model of schizophrenia.
    BibTeX:
    @article{Lipska1995,
      author = {Lipska, BK and Swerdlow, NR and Geyer, MA and Jaskiw, GE and Braff, DL and Weinberger, DR},
      title = {Neonatal excitotoxic hippocampal damage in rats causes post pubertal changes in prepulse inhibition of startle and its disruption by apomorphine},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1995},
      volume = {122},
      number = {1},
      pages = {35-43}
    }
    
    Lisman, J. & Grace, A. The hippocampal-VTA loop: Controlling the entry of information into long-term memory {2005} NEURON
    Vol. {46}({5}), pp. {703-713} 
    article DOI  
    Abstract: In this article we develop the concept that the hippocampus and the midbrain dopaminergic neurons of the ventral tegmental area (VTA) form a functional loop. Activation of the loop begins when the hippocampus detects newly arrived information that is not already stored in its long-term memory. The resulting novelty signal is conveyed through the subiculum, accumbens, and ventral pallidum to the VTA where it contributes (along with salience and goal information) to the novelty-dependent firing of these cells. In the upward arm of the loop, dopamine (DA) is released within the hippocampus; this produces an enhancement of LTP and learning. These findings support a model whereby the hippocampal-VTA loop regulates the entry of information into long-term memory.
    BibTeX:
    @article{Lisman2005,
      author = {Lisman, JE and Grace, AA},
      title = {The hippocampal-VTA loop: Controlling the entry of information into long-term memory},
      journal = {NEURON},
      year = {2005},
      volume = {46},
      number = {5},
      pages = {703-713},
      doi = {{10.1016/j.neuron.2005.05.002}}
    }
    
    LYNESS, W., FRIEDLE, N. & MOORE, K. DESTRUCTION OF DOPAMINERGIC NERVE-TERMINALS IN NUCLEUS ACCUMBENS - EFFECT ON D-AMPHETAMINE SELF-ADMINISTRATION {1979} PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
    Vol. {11}({5}), pp. {553-556} 
    article  
    BibTeX:
    @article{LYNESS1979,
      author = {LYNESS, WH and FRIEDLE, NM and MOORE, KE},
      title = {DESTRUCTION OF DOPAMINERGIC NERVE-TERMINALS IN NUCLEUS ACCUMBENS - EFFECT ON D-AMPHETAMINE SELF-ADMINISTRATION},
      journal = {PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR},
      year = {1979},
      volume = {11},
      number = {5},
      pages = {553-556}
    }
    
    MAILLEUX, P. & VANDERHAEGHEN, J. DISTRIBUTION OF NEURONAL CANNABINOID RECEPTOR IN THE ADULT-RAT BRAIN - A COMPARATIVE RECEPTOR-BINDING AUTORADIOGRAPHY AND INSITU HYBRIDIZATION HISTOCHEMISTRY {1992} NEUROSCIENCE
    Vol. {48}({3}), pp. {655-668} 
    article  
    Abstract: The neuronal distribution of cannabinoid receptor in the adult rat brain is reported, combining receptor binding radioautography using the synthetic psychoative cannabinoid ligand CP55,940 with in situ hybridization histochemistry using oligonucleotide probes complementary to rat cannabinoid receptor cDNA. In the cerebral cortex, especially in the frontal and cingulate cortex, dense binding was found in layers I and VI together with slight mRNA levels in a majority of both pyramidal and non-pyramidal-shaped neurons and of high mRNA levels in a moderate number of non-pyramidal-shaped neurons especially in layers II-III and V-VI. In the hippocampal dentate gyrus, very dense staining was found in the molecular layer together with high mRNA levels in a moderate number of hilar neurons close to the granular layer. In Ammon's horn, especially in the CA3 sector, very dense binding was found in the dendritic layers together with slight mRNA levels in the majority of the pyramidal cells and high mRNA levels in a moderate number of interneurons. In the basal ganglia, binding was very dense in the lateral putamen, substantia nigra pars reticulata, globus pallidus and entopeduncular nucleus, moderate in the medial putamen and caudate; and slight in the accumbens, together with slight to moderate mRNA levels in the striatal medium-sized neurons. Together with slight binding, slight to moderate mRNA levels were found in the majority of the neurons in the subthalamic nucleus. No binding and mRNA were found in the substantia nigra pars compacta and ventral tegmental area. Slight to moderate binding was found together with slight to moderate mRNA levels in the majority of neurons in the anterior olfactory nucleus; septum, especially medial septum and diagonal band of Broca; amygdala, especially basolateral amygdala; lateral habenula; ventromedial hypothalamic nucleus; lateral interpenduncular nucleus; central gray, dorsal cochlear nucleus; parabrachial nucleus; dorsal pontine tegmentum; pontine nuclei; commissural part of the nucleus tractus solitarius; inferior olive and dorsal horn of the spinal cord. In the cerebellum, very dense binding was found in the molecular layer together with slight mRNA levels in the majority of the granule cells and moderate mRNA levels in the basket and stellate cells. In conclusion, this study provides, for the first time, indirect assessment of the neurons containing cannabinoid receptor in the entire adult rat brain and will serve as a basis for future direct morphological confirmation using receptor immunohistochemistry and for functional studies.
    BibTeX:
    @article{MAILLEUX1992,
      author = {MAILLEUX, P and VANDERHAEGHEN, JJ},
      title = {DISTRIBUTION OF NEURONAL CANNABINOID RECEPTOR IN THE ADULT-RAT BRAIN - A COMPARATIVE RECEPTOR-BINDING AUTORADIOGRAPHY AND INSITU HYBRIDIZATION HISTOCHEMISTRY},
      journal = {NEUROSCIENCE},
      year = {1992},
      volume = {48},
      number = {3},
      pages = {655-668}
    }
    
    Maldonado, R., Saiardi, A., Valverde, O., Samad, T., Roques, B. & Borrelli, E. Absence of opiate rewarding effects in mice lacking dopamine D2 receptors {1997} NATURE
    Vol. {388}({6642}), pp. {586-589} 
    article  
    Abstract: Dopamine receptors have been implicated in the behavioural response to drugs of abuse. These responses are mediated particularly by the mesolimbic dopaminergic pathway arising in the ventral tegmental area and projecting to the limbic system, The rewarding properties of opiates(1) and the somatic expression of morphine abstinence(2) have been related to changes in mesolimbic dopaminergic activity that could constitute the neural substrate for opioid addiction(3), These adaptive responses to repeated morphine administration have been investigated in mice with a genetic disruption of the dopaminergic D2 receptors(4). Although the behavioural expression of morphine withdrawal was unchanged in these mice, a total suppression of morphine rewarding properties was observed in a place-preference test. This effect is specific to the drug, as mice lacking D2 receptors behaved the same as wild-type mice when food is used as reward, We conclude that the D2 receptor plays a crucial role in the motivational component of drug addiction.
    BibTeX:
    @article{Maldonado1997,
      author = {Maldonado, R and Saiardi, A and Valverde, O and Samad, TA and Roques, BP and Borrelli, E},
      title = {Absence of opiate rewarding effects in mice lacking dopamine D2 receptors},
      journal = {NATURE},
      year = {1997},
      volume = {388},
      number = {6642},
      pages = {586-589}
    }
    
    MALDONADO, R., STINUS, L., GOLD, L. & KOOB, G. ROLE OF DIFFERENT BRAIN STRUCTURES IN THE EXPRESSION OF THE PHYSICAL MORPHINE-WITHDRAWAL SYNDROME {1992} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {261}({2}), pp. {669-677} 
    article  
    Abstract: The aim of this study was to investigate the neuroanatomical regions implicated in the expression of the physical signs of morphine withdrawal by using local intracerebral injections of methylnaloxonium in dependent rats. Guide cannulas were implanted and aimed at the lateral ventricle, nucleus accumbens, central amygdala, anterior hypothalamus, medial thalamus, periaqueductal gray matter, locus coeruleus and nucleus raphe magnus. After surgery, rats were made physically dependent by s.c. implantation of two 75-mg morphine pellets. Methylnaloxonium, a quaternary derivative of naloxone (31-1000 ng), was administered 72 hr after pellet implantation. Methylnaloxonium administered i.c.v. induced a withdrawal syndrome similar to systemic naloxone, although several signs such as diarrhea, salivation, lacrimation and rhinorrhea did not appear, suggesting possible peripheral mediation. The most sensitive site for methylnaloxonium-precipitated withdrawal was the locus coeruleus. Signs such as jumping, rearing and locomotor activity were particularly frequent after methylnaloxonium injections into the locus coeruleus. Rearing and locomotor activity were also strongly increased after methylnaloxonium administration into the periaqueductal gray matter. Wet dog shakes were mainly observed after methylnaloxonium administration into the anterior preoptic hypothalamus and nucleus raphe magnus. Injections of methylnaloxonium into the amygdala produced a weak withdrawal syndrome, and the nucleus accumbens and medial thalamus were the least sensitive structures. These results suggest that the locus coeruleus, and secondarily the periaqueductal gray matter, play an important role in the precipitation of the physical signs of opiate withdrawal, mainly in the expression of its motor component. The expression of other signs of withdrawal appear to be multisite determined.
    BibTeX:
    @article{MALDONADO1992,
      author = {MALDONADO, R and STINUS, L and GOLD, LH and KOOB, GF},
      title = {ROLE OF DIFFERENT BRAIN STRUCTURES IN THE EXPRESSION OF THE PHYSICAL MORPHINE-WITHDRAWAL SYNDROME},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1992},
      volume = {261},
      number = {2},
      pages = {669-677}
    }
    
    MALDONADOIRIZARRY, C., SWANSON, C. & KELLEY, A. GLUTAMATE RECEPTORS IN THE NUCLEUS-ACCUMBENS SHELL CONTROL FEEDING-BEHAVIOR VIA THE LATERAL HYPOTHALAMUS {1995} JOURNAL OF NEUROSCIENCE
    Vol. {15}({10}), pp. {6779-6788} 
    article  
    Abstract: The nucleus accumbens is a brain region considered to be important in the regulation of appetitive behavior and reinforcement. The accumbens receives afferent input from corticolimbic and thalamic structures, which is primarily coded by excitatory amino acids (EAAs). The present studies investigated the role of EAA input to the nucleus accumbens in feeding behavior in rats, in two recently characterized subregions of the accumbens, the `'core'' and `'shell.'' In the first series of experiments, it was shown that blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate glutamate receptors in the medial part of the accumbens, corresponding to the medial shell subregion, resulted in a pronounced feeding response. Bilateral microinfusion of 6,7-dinitroquinoxaline-2,3-dione (DNQX, 0.25-0.75 mu g/0.5 mu l), 6-cyano-7-nitroquinoxaline (CNQX, 0.75-1.5 mu g), and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-(F) quinoxaline (NBQX, 0.2-1.0 mu g) markedly stimulated food intake immediately following infusion, in a dose-dependent manner. Infusion of DNQX into the central accumbens region, corresponding to the core, did not elicit feeding. Infusion of the NMDA antagonists 2-amino-5-phosphonopentanoic acid (AP-5) and MK-801 (dizocilpine maleate) did not elicit feeding in either region. The feeding response to DNQX was blocked by local coinfusion of AMPA. Systemic pretreatment with naltrexone (5 mg/kg) had no effect on the DNQX-feeding response; however, prior systemic administration of both D-1 and D-2 antagonists reduced the response by half, suggesting a modulatory role for dopamine in the response. Moreover, the feeding response was completely inhibited by concurrent infusion of the GABA(A) agonist muscimol (10, 25 ng) into the lateral hypothalamus, a major projection area of the accumbens shell. These findings demonstrate a selective role for non-NMDA receptors in the nucleus accumbens shell in ingestive behavior, and suggest an important functional link between two major brain regions involved in reward, the nucleus accumbens and lateral hypothalamus.
    BibTeX:
    @article{MALDONADOIRIZARRY1995,
      author = {MALDONADOIRIZARRY, CS and SWANSON, CJ and KELLEY, AE},
      title = {GLUTAMATE RECEPTORS IN THE NUCLEUS-ACCUMBENS SHELL CONTROL FEEDING-BEHAVIOR VIA THE LATERAL HYPOTHALAMUS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1995},
      volume = {15},
      number = {10},
      pages = {6779-6788}
    }
    
    MANSOUR, A., FOX, C., BURKE, S., AKIL, H. & WATSON, S. IMMUNOHISTOCHEMICAL LOCALIZATION OF THE CLONED MU-OPIOID RECEPTOR IN THE RAT CNS {1995} JOURNAL OF CHEMICAL NEUROANATOMY
    Vol. {8}({4}), pp. {283-305} 
    article  
    Abstract: Three opioid receptor types have recently been cloned that correspond to the pharmacologically defined mu, delta and K-1 receptors. In situ hybridization studies suggest that the opioid receptor mRNAs that encode these receptors have distinct distributions in the central nervous system that correlate well with their known functions. In the present study polyclonal antibodies were generated to the C terminal 63 amino acids of the cloned mu receptor (335-398) to examine the distribution of the mu receptor-like protein with immunohistochemical techniques. mu receptor-like immunoreactivity is widely distributed in the rat central nervous system with immunoreactive fibers and/or perikarya in such regions as the neocortex, the striatal patches and subcallosal streak, nucleus accumbens, lateral and medial septum, endopiriform nucleus, globus pallidus and ventral pallidum, amygdala, hippocampus, presubiculum, thalamic and hypothalamic nuclei, superior and inferior colliculi, central grey, substantia nigra, ventral tegmental area, interpeduncular nucleus, medial terminal nucleus of the accessory optic tract, raphe nuclei, nucleus of the solitary tract, spinal trigeminal nucleus, dorsal motor nucleus of vagus, the spinal cord and dorsal root ganglia. In addition, two major neuronal pathways, the fasciculus retroflexus and the stria terminalis, exhibit densely stained axonal fibers. While this distribution is in excellent agreement with the known mu receptor binding localization, a few regions, such as neocortex and cingulate cortex, basolateral amygdala, medial geniculate nucleus and the medial preoptic area fail to show a good correspondence. Several explanations are provided to interpret these results, and the anatomical and functional implications of these findings are discussed.
    BibTeX:
    @article{MANSOUR1995,
      author = {MANSOUR, A and FOX, CA and BURKE, S and AKIL, H and WATSON, SJ},
      title = {IMMUNOHISTOCHEMICAL LOCALIZATION OF THE CLONED MU-OPIOID RECEPTOR IN THE RAT CNS},
      journal = {JOURNAL OF CHEMICAL NEUROANATOMY},
      year = {1995},
      volume = {8},
      number = {4},
      pages = {283-305}
    }
    
    MANSOUR, A., FOX, C., BURKE, S., MENG, F., THOMPSON, R., AKIL, H. & WATSON, S. MU-OPIOID, DELTA-OPIOID, AND KAPPA-OPIOID RECEPTOR MESSENGER-RNA EXPRESSION IN THE RAT CNS - AN IN-SITU HYBRIDIZATION STUDY {1994} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {350}({3}), pp. {412-438} 
    article  
    Abstract: The mu, delta, and kappa opioid receptors are the three main types of opioid receptors found in the central nervous system (CNS) and periphery. These receptors and the peptides with which they interact are important in a number of physiological functions, including analgesia, respiration, and hormonal regulation. This study examines the expression of mu, delta, and kappa receptor mRNAs in the rat brain and spinal cord using in situ hybridization techniques. Tissue sections were hybridized with S-35-labeled cRNA probes to the rat mu (744-1,064 b), delta (304-1,287 b), and kappa (1,351-2,124 b) receptors. Each mRNA demonstrates a distinct anatomical distribution that corresponds well to known receptor binding distributions. Cells expressing mu receptor mRNA are localized in such regions as the olfactory bulb, caudate-putamen, nucleus accumbens, lateral and medial septum, diagonal band of Broca, bed nucleus of the stria terminalis, most thalamic nuclei, hippocampus, amygdala, medial preoptic area, superior and inferior colliculi, central gray, dorsal and median raphe, raphe magnus, locus coeruleus, parabrachial nucleus, pontine and medullary reticular nuclei, nucleus ambiguus, nucleus of the solitary tract, nucleus gracilis and cuneatus, dorsal motor nucleus of vagus, spinal cord, and dorsal root ganglia. Cellular localization of delta receptor mRNA varied from mu, or kappa, with expression in such regions as the olfactory bulb, allo- and neocortex, caudate-putamen, nucleus accumbens, olfactory tubercle, ventromedial hypothalamus, hippocampus, amygdala, red nucleus, pontine nuclei, reticulotegmental nucleus, motor and spinal trigeminal, linear nucleus of the medulla, lateral reticular nucleus, spinal cord, and dorsal root ganglia. Cells expressing kappa receptor mRNA demonstrate a third pattern of expression, with cells localized in regions such as the claustrum, endopiriform nucleus, nucleus accumbens, olfactory tubercle, medial preoptic area, bed nucleus of the stria terminalis, amygdala, most hypothalamic nuclei, median eminence, infundibulum, substantia nigra, ventral tegmental area, raphe nuclei, paratrigeminal and spinal trigeminal, nucleus of the solitary tract, spinal cord, and dorsal root ganglia. These findings are discussed in relation to the physiological functions associated with the opioid receptors. (C) 1994 Wiley-Liss, Inc.
    BibTeX:
    @article{MANSOUR1994,
      author = {MANSOUR, A and FOX, CA and BURKE, S and MENG, F and THOMPSON, RC and AKIL, H and WATSON, SJ},
      title = {MU-OPIOID, DELTA-OPIOID, AND KAPPA-OPIOID RECEPTOR MESSENGER-RNA EXPRESSION IN THE RAT CNS - AN IN-SITU HYBRIDIZATION STUDY},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1994},
      volume = {350},
      number = {3},
      pages = {412-438}
    }
    
    MANSOUR, A., FOX, C., THOMPSON, R., AKIL, H. & WATSON, S. MU-OPIOID RECEPTOR MESSENGER-RNA EXPRESSION IN THE RAT CNS - COMPARISON TO MU-RECEPTOR BINDING {1994} BRAIN RESEARCH
    Vol. {643}({1-2}), pp. {245-265} 
    article  
    Abstract: The distribution of cells expressing mu-receptor mRNA and mu-receptor binding sites were compared in brain and spinal cord tissue sections using a combination of in situ hybridization and receptor autoradiographic techniques. mu-Receptor mRNA was visualized with a S-35-labeled cRNA probe directed to transmembrane III-VI of the rat mu-receptor, while mu-receptor binding sites were labeled with the mu-selective ligand [H-3]DAMGO. A high correspondence between the mu-receptor mRNA and receptor binding distributions was observed in the nucleus of the accessory olfactory bulb, anterior olfactory nuclei, striatal patches of the nucleus accumbens and caudate-putamen, endopiriform nucleus, claustrum, diagonal band of Broca, globus pallidus, ventral pallidum, bed nucleus of stria terminalis, most thalamic nuclei, medial and posteriocortical medial amygdala, lateral, dorsomedial, posterior and mammillary nuclei of the hypothalamus, presubiculum, subiculum, rostral interpeduncular nucleus, median raphe, inferior colliculus, parabrachial nucleus, locus coeruleus, central grey, nucleus ambiguus, nucleus of the solitary tract, nucleus gracilis, nucleus cuneatus, and the dorsal motor nucleus of vagus. Differences in mu-receptor mRNA and receptor binding distributions were observed in several regions, including the olfactory bulb, cortex, hippocampus, superior colliculus, spinal trigeminal nucleus, cochlear nucleus and spinal cord, and may be due to mu-receptor transport to presynaptic terminals.
    BibTeX:
    @article{MANSOUR1994a,
      author = {MANSOUR, A and FOX, CA and THOMPSON, RC and AKIL, H and WATSON, SJ},
      title = {MU-OPIOID RECEPTOR MESSENGER-RNA EXPRESSION IN THE RAT CNS - COMPARISON TO MU-RECEPTOR BINDING},
      journal = {BRAIN RESEARCH},
      year = {1994},
      volume = {643},
      number = {1-2},
      pages = {245-265}
    }
    
    Mansvelder, H., Keath, J. & McGehee, D. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas {2002} NEURON
    Vol. {33}({6}), pp. {905-919} 
    article  
    Abstract: A single nicotine exposure increases dopamine levels in the mesolimbic reward system for hours, but nicotine concentrations experienced by smokers desensitize nAChRs on dopamine neurons in seconds to minutes. Here, we show that persistent modulation of both GABAergic and glutamatergic synaptic transmission by nicotine can contribute to the sustained increase in dopamine neuron excitability. Nicotine enhances GABAergic transmission transiently, which is followed by a persistent depression of these inhibitory inputs due to nAChR desensitization. Simultaneously, nicotine enhances glutamatergic transmission through nAChRs that desensitize less than those on GABA neurons. The net effect is a shift toward excitation of the dopamine reward system. These results suggest that spatial and temporal differences in nicotinic receptor activity on both excitatory and inhibitory neurons in reward areas coordinate to reinforce nicotine self-administration.
    BibTeX:
    @article{Mansvelder2002,
      author = {Mansvelder, HD and Keath, JR and McGehee, DS},
      title = {Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas},
      journal = {NEURON},
      year = {2002},
      volume = {33},
      number = {6},
      pages = {905-919}
    }
    
    Mansvelder, H. & McGehee, D. Long-term potentiation of excitatory inputs to brain reward areas by nicotine {2000} NEURON
    Vol. {27}({2}), pp. {349-357} 
    article  
    Abstract: Nicotine reinforces smoking behavior by activating nicotinic acetylcholine receptors (nAChRs) in the mid-brain dopaminergic (DA) reward centers, including the ventral tegmental area (VTA). Although nicotine induces prolonged excitation of the VTA in vivo, the nAChRs on the DA neurons desensitize in seconds. Here, we show that activation of nAChRs on presynaptic terminals in the VTA enhances glutamatergic inputs to DA neurons. Under conditions where the released glutamate can activate NMDA receptors, long-term potentiation (LTP) of the excitatory inputs is induced. Both the short- and the long-term effects of nicotine required activation of presynaptic alpha 7 subunit-containing nAChRs. These results can explain the long-term excitation of brain reward areas induced by a brief nicotine exposure. They also show that nicotine alters synaptic function through mechanisms that are linked to learning and memory.
    BibTeX:
    @article{Mansvelder2000,
      author = {Mansvelder, HD and McGehee, DS},
      title = {Long-term potentiation of excitatory inputs to brain reward areas by nicotine},
      journal = {NEURON},
      year = {2000},
      volume = {27},
      number = {2},
      pages = {349-357}
    }
    
    MARKOU, A., WEISS, F., GOLD, L., CAINE, S., SCHULTEIS, G. & KOOB, G. ANIMAL-MODELS OF DRUG CRAVING {1993} PSYCHOPHARMACOLOGY
    Vol. {112}({2-3}), pp. {163-182} 
    article  
    Abstract: Drug craving, the desire to experience the effect(s) of a previously experienced psychoactive substance, has been hypothesized to contribute significantly to continued drug use and relapse after a period of abstinence in humans. In more theoretical terms, drug craving can be conceptualized within the framework of incentive motivational theories of behavior and be defined as the incentive motivation to self-administer a psychoactive substance. The incentive-motivational value of drugs is hypothesized to be determined by a continuous interaction between the hedonic rewarding properties of drugs (incentive) and the motivational state of the organism (organismic state). In drug-dependent individuals, the incentive-motivational value of drugs (i.e., drug craving) is greater compared to non-drug-dependent individuals due to the motivational state (i.e., withdrawal) developed with repeated drug administration. In this conceptual framework, animal models of drug craving would reflect two aspects of the incentive motivation to self-administer a psychoactive substance. One aspect would be the unconditioned incentive (reinforcing) value of the drug itself. The other aspect would be relatively independent of the direct (unconditioned) incentive value of the drug itself and could be reflected in the ability of previously neutral stimuli to acquire conditioned incentive properties that could elicit drug-seeking and drug-taking behavior. Animal models of drug craving that permit the investigation of the behavioral and neurobiological components of these two aspects of drug craving are reviewed and evaluated. The models reviewed are the progressive ratio, choice, extinction, conditioned reinforcement and second-order schedule paradigms. These animal models are evaluated according to two criteria that are established herein as necessary and sufficient criteria for the evaluation of animal models of human psychopathology: reliability and predictive validity. The development of animal models of drug craving will have heuristic value and allow a systematic investigation of the neurobiological mechanisms of craving.
    BibTeX:
    @article{MARKOU1993,
      author = {MARKOU, A and WEISS, F and GOLD, LH and CAINE, SB and SCHULTEIS, G and KOOB, GF},
      title = {ANIMAL-MODELS OF DRUG CRAVING},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1993},
      volume = {112},
      number = {2-3},
      pages = {163-182}
    }
    
    Marshall, D., Redfern, P. & Wonnacott, S. Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: Comparison of naive and chronic nicotine-treated rats {1997} JOURNAL OF NEUROCHEMISTRY
    Vol. {68}({4}), pp. {1511-1519} 
    article  
    Abstract: The modulation of dopamine release by presynaptic nicotinic receptors in vitro is well established, but the significance of this effect in vivo is unclear. We have characterised the effect of nicotine, locally applied via a microdialysis probe, on dopamine release from the terminal regions of three ascending dopaminergic pathways in conscious, freely moving rats, Nicotine caused a dose-dependent increase in dopamine release in the striatum, the nucleus accumbens, and, to a lesser extent, the frontal cortex, Metabolite levels were unaltered by any concentration of nicotine, Prior administration of mecamylamine via the probe abolished the nicotine-evoked increase in dopamine release, confirming the mediation of nicotinic receptors. The dose dependence of mecamylamine-sensitive, nicotine-evoked dopamine release was similar in all three brain regions. However, 10(-5) M tetrodotoxin totally blocked nicotine-stimulated dopamine release in the striatum and the accumbens but not the cortex, Daily subcutaneous injections of nicotine (0.4 mg kg(-1) for 7 days) increased the response to a subsequent local application of nicotine in the striatum, and a similar trend was found in the other brain areas, The same daily dose of nicotine given as a continuous infusion had no effect, whereas infusion of 4 mg kg(-1) day(-1) increased the response to a subsequent nicotine challenge. The localisation and regulation of nicotinic receptors in the terminal fields of dopaminergic pathways are discussed.
    BibTeX:
    @article{Marshall1997,
      author = {Marshall, DL and Redfern, PH and Wonnacott, S},
      title = {Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: Comparison of naive and chronic nicotine-treated rats},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1997},
      volume = {68},
      number = {4},
      pages = {1511-1519}
    }
    
    Martin-Schild, S., Gerall, A., Kastin, A. & Zadina, J. Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent {1999} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {405}({4}), pp. {450-471} 
    article  
    Abstract: Endomorphins are endogenous peptides that have high affinity and selectivity for the mu-opiate receptor and potent analgesic activity. The distributions of endomorphin 1 (Tyr-Pro-Trp-Phe-NH2; EM1) and endomorphin 2 (Tyr-Pro-Phe-Phe-NH2; EM2) in the rat central nervous system mere determined by immunocytochemistry with two antisera, each demonstrating clear preference for the target antigen. Perikarya expressing EM2-like immunoreactivity were present in the posterior hypothalamus, whereas those expressing EM1-like immunoreactivity were present in both the posterior hypothalamus and the nucleus of the solitary tract (NTS). EM1-like immunoreactivity was more widely and densely distributed throughout the brain than was EM2-like immunoreactivity, whereas EM2-like immunoreactivity was more prevalent in the spinal cord than was EM1-like immunoreactivity. The greatest density of EM1-like-immunoreactive fibers was detected in the parabrachial nucleus and the NTS, with notable staining in the septum, diagonal band, bed nucleus of the stria terminalis, organum vasculosum, nucleus of Meynert, paraventricular thalamic nucleus, posterior hypothalamic nucleus, periaqueductal gray, locus coeruleus, nucleus accumbens, and amygdala. The greatest density of EM2-like-immunoreactive fibers was detected in the superficial laminae of the spinal cord dorsal horn and the nucleus of the spinal trigeminal tract. The overall pattern of immunoreactivities was similar in rat, mouse, and guinea pig, but some differences were observed. In many but not in all locations, immunoreactive fibers were prominently present in regions in which mu p receptors are reported to be concentrated. The neuroanatomical results suggest that endomorphins participate in modulating nociceptive and autonomic nervous system processes and responsiveness to stress. Published 1999 Wiley-Liss, Inc.dagger
    BibTeX:
    @article{Martin-Schild1999,
      author = {Martin-Schild, S and Gerall, AA and Kastin, AJ and Zadina, JE},
      title = {Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1999},
      volume = {405},
      number = {4},
      pages = {450-471}
    }
    
    Maskos, U., Molles, B., Pons, S., Besson, M., Guiard, B., Guilloux, J., Evrard, A., Cazala, P., Cormier, A., Mameli-Engvall, M., Dufour, N., Cloez-Tayarani, I., Bemelmans, A., Mallet, J., Gardier, A., David, V., Faure, P., Granon, S. & Changeux, J. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors {2005} NATURE
    Vol. {436}({7047}), pp. {103-107} 
    article DOI  
    Abstract: Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction(1), but nicotine is also known to enhance cognitive performance(2). Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the beta 2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying beta 2-subunit deletions(3,4). We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that beta 2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.
    BibTeX:
    @article{Maskos2005,
      author = {Maskos, U and Molles, BE and Pons, S and Besson, M and Guiard, BP and Guilloux, JP and Evrard, A and Cazala, P and Cormier, A and Mameli-Engvall, M and Dufour, N and Cloez-Tayarani, I and Bemelmans, AP and Mallet, J and Gardier, AM and David, V and Faure, P and Granon, S and Changeux, JP},
      title = {Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors},
      journal = {NATURE},
      year = {2005},
      volume = {436},
      number = {7047},
      pages = {103-107},
      doi = {{10.1038/nature03694}}
    }
    
    Mazzucchelli, C., Vantaggiato, C., Ciamei, A., Fasano, S., Pakhotin, P., Krezel, W., Welzl, H., Wolfer, D., Pages, G., Valverde, O., Marowsky, A., Porrazzo, A., Orban, P., Maldonado, R., Ehrengruber, M., Cestari, V., Lipp, H., Chapman, P., Pouyssegur, J. & Brambilla, R. Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory {2002} NEURON
    Vol. {34}({5}), pp. {807-820} 
    article  
    Abstract: Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK. Consistently, such activity change is responsible for the hypersensitivity of ERK1 mutant mice to the rewarding properties of morphine. Our results reveal an unexpected complexity of ERK-dependent signaling in the brain and a critical regulatory role for ERK1 in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.
    BibTeX:
    @article{Mazzucchelli2002,
      author = {Mazzucchelli, C and Vantaggiato, C and Ciamei, A and Fasano, S and Pakhotin, P and Krezel, W and Welzl, H and Wolfer, DP and Pages, G and Valverde, O and Marowsky, A and Porrazzo, A and Orban, PC and Maldonado, R and Ehrengruber, MU and Cestari, V and Lipp, HP and Chapman, PF and Pouyssegur, J and Brambilla, R},
      title = {Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory},
      journal = {NEURON},
      year = {2002},
      volume = {34},
      number = {5},
      pages = {807-820}
    }
    
    McBride, W., Murphy, J. & Ikemoto, S. Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies {1999} BEHAVIOURAL BRAIN RESEARCH
    Vol. {101}({2}), pp. {129-152} 
    article  
    Abstract: Intracranial self-administration (ICSA) and intracranial place conditioning (ICPC) methodologies have been mainly used to study drug reward mechanisms, but they have also been applied toward examining brain reward mechanisms. ICSA studies in rodents have established that the ventral tegmental area (VTA) is a site supporting morphine and ethanol reinforcement. ICPC studies confirmed that injection of morphine into the VTA produces conditioned place preference (CPP). Further confirmation that activation of opioid receptors within the VTA is reinforcing comes from the findings that the endogenous opioid peptide met-enkephalin injected into the VTA produces CPP, and that the mu- and delta-opioid agonists, DAMGO and DPDPE, are self-infused into the VTA. Activation of the VTA dopamine (DA) system may produce reinforcing effects in general because (a) neurotensin is self-administered into the VTA, and injection of neurotensin into the VTA produces CPP and enhances DA release in the nucleus accumbens (NAC), and (b) GABA(A) antagonists are self-administered into the anterior VTA and injections of GABA(A) antagonists into the anterior VTA enhance DA release in the NAG. The NAC also appears to have a major role in brain reward mechanisms, whereas most data from ICSA and ICPC studies do not support an involvement of the caudate-putamen in reinforcement processes. Rodents will self-infuse a variety of drugs of abuse (e.g, amphetamine, morphine, phencyclidine and cocaine) into the NAG, and this occurs primarily in the shell region. ICPC studies also indicate that injection of amphetamine into the shell portion of the NAC produces CPP. Activation of the DA system within the shell subregion of the NAC appears to play a key role in brain reward mechanisms. Rats will ICSA the DA uptake blocker, nomifensine, into the NAC shell; co-infusion with a D-2 antagonist can block this behavior. In addition, rats will self-administer a mixture of a D-1 plus a D-2 agonist into the shell, but not the core, region of the NAG. The ICSA of this mixture can be blocked with the co-infusion of either a D-1 or a D-2 antagonist. However, the interactions of other transmitter systems within the NAC may also play key roles because NMDA antagonists and the muscarinic agonist carbachol are self-infused into the NAG. The medial prefrontal (MPF) cortex supports the ICSA of cocaine and phencyclidine. The DA system also seems to play a role in this behavior since cocaine self-infusion into the MPF cortex can be blocked by co-infusing a D-2 antagonist, or with 6-OHDA lesions of the MPF cortex. Limited studies have been conducted on other CNS regions to elucidate their role in brain and drug reward mechanisms using ICSA or ICPC procedures. Among these regions, ICPC findings suggest that cocaine and amphetamine are rewarding in the rostral ventral pallidum (VP); ICSA and ICPC studies indicate that morphine is rewarding in the dorsal hippocampus, central gray and lateral hypothalamus. Finally, substance P mediated systems within the caudal VP (nucleus basalis magnocellularis) and serotonin systems of the dorsal and median raphe nuclei may also be important anatomical components involved in brain reward mechanisms. Overall, the ICSA and ICPC studies indicate that there are a number of receptors, neuronal pathways, and discrete CNS sites involved in brain reward mechanisms. (C) 1999 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{McBride1999,
      author = {McBride, WJ and Murphy, JM and Ikemoto, S},
      title = {Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {1999},
      volume = {101},
      number = {2},
      pages = {129-152}
    }
    
    McClung, C. & Nestler, E. Regulation of gene expression and cocaine reward by CREB and Delta FosB {2003} NATURE NEUROSCIENCE
    Vol. {6}({11}), pp. {1208-1215} 
    article DOI  
    Abstract: DeltaFosB (a truncated form of FosB) and CREB (cAMP response element binding protein) are transcription factors induced in the brain's reward pathways after chronic exposure to drugs of abuse. However, their mechanisms of action and the genes they regulate remain unclear. Using microarray analysis in the nucleus accumbens of inducible transgenic mice, we found that CREB and a dominant-negative CREB have opposite effects on gene expression, as do prolonged expression of DeltaFosB and the activator protein-1 (AP-1) antagonist DeltacJun. However, unlike CREB, short-term and prolonged DeltaFosB induction had opposing effects on gene expression. Gene expression induced by short-term DeltaFosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged DeltaFosB expression increased drug reward. Gene expression after a short cocaine treatment was more dependent on CREB, whereas gene expression after a longer cocaine treatment became increasingly DeltaFosB dependent. These findings help define the molecular functions of CREB and DeltaFosB and identify clusters of genes that contribute to cocaine addiction.
    BibTeX:
    @article{McClung2003,
      author = {McClung, CA and Nestler, EJ},
      title = {Regulation of gene expression and cocaine reward by CREB and Delta FosB},
      journal = {NATURE NEUROSCIENCE},
      year = {2003},
      volume = {6},
      number = {11},
      pages = {1208-1215},
      doi = {{10.1038/nn1143}}
    }
    
    MCDONALD, A. TOPOGRAPHICAL ORGANIZATION OF AMYGDALOID PROJECTIONS TO THE CAUDATOPUTAMEN, NUCLEUS-ACCUMBENS, AND RELATED STRIATAL-LIKE AREAS OF THE RAT-BRAIN {1991} NEUROSCIENCE
    Vol. {44}({1}), pp. {15-33} 
    article  
    Abstract: The topographical organization of amygdaloid projections to the caudatoputamen, nucleus accumbens, and lateral portions of the bed nucleus of the stria terminalis and central amygdaloid nucleus was investigated, in the mt, using the retrograde transport of wheat germ agglutinin-conjugated horseradish peroxidase. Although the caudatoputamen and nucleus accumbens are the principal components of the striatum, there is evidence that lateral portions of the bed nucleus of the stria terminalis and central amygdaloid nucleus may be striatal-like structures. The basolateral nucleus was the main source of amygdaloid fibers to all of these structures. In many instances labeled areas of the basolateral nucleus were continuous with labeled areas in the adjacent lateral and basomedial nuclei. Amygdaloid neurons projecting to the striatum and striatal-like areas exhibited an overlapping topographical organization. In general, the medial-to-lateral coordinate in the striatum corresponds to the medial-to-lateral coordinate in the basolateral nucleus. There was also a partial reversed sagittal topography in that the caudal caudatoputamen receives its principal projection from the rostral basolateral nucleus. However, the rostral basolateral nucleus had a stronger projection to the rostral caudatoputamen and lateral nucleus accumbens than the caudal basolateral nucleus. The principal striatal projection of the caudal basolateral nucleus was to the medial nucleus accumbens. Amygdaloid labeling produced by injections into the medial nucleus accumbens was very similar to that seen with injections into the lateral portions of the bed nucleus of the stria terminalis and central amygdaloid nucleus. The retrograde amygdaloid labeling seen in this investigation, when compared to labeling seen with cortical injections in previous studies, suggests that specific amygdaloid domains project to particular cortical areas as well as to the principal striatal targets of these same areas.
    BibTeX:
    @article{MCDONALD1991,
      author = {MCDONALD, AJ},
      title = {TOPOGRAPHICAL ORGANIZATION OF AMYGDALOID PROJECTIONS TO THE CAUDATOPUTAMEN, NUCLEUS-ACCUMBENS, AND RELATED STRIATAL-LIKE AREAS OF THE RAT-BRAIN},
      journal = {NEUROSCIENCE},
      year = {1991},
      volume = {44},
      number = {1},
      pages = {15-33}
    }
    
    McFarland, K. & Kalivas, P. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior {2001} JOURNAL OF NEUROSCIENCE
    Vol. {21}({21}), pp. {8655-8663} 
    article  
    Abstract: The role of limbic-striato-pallidal circuitry in cocaine-induced reinstatement was evaluated. The transient inhibition of brain nuclei associated with motor systems [including the ventral tegmental area (VTA), dorsal prefrontal cortex (dPFC), core of the nucleus accumbens (NAcore), and ventral pallidum (VP)] prevented cocaine-induced reinstatement. However, only the VP proved to be necessary for food reinstatement, suggesting that the identified circuit is specific to drug-related reinstatement. Supporting the possibility that the VTA-dPFC-NAcore-VP is a series circuit mediating reinstatement, simultaneous unilateral microinjection of GABA agonists into the dPFC in one hemisphere and into the VP in the contralateral hemisphere abolished cocaine reinstatement. Although dopamine projections from the VTA innervate all three forebrain nuclei, the blockade of dopamine receptors only in the dPFC antagonized cocaine-induced reinstatement. Furthermore, DA administration into the dPFC was sufficient to elicit a reinstatement in drug-related responding. These data demonstrate that dopamine release in the dPFC initiates a dPFC-NAcore-VP series circuit that mediates cocaine-induced drug-seeking behavior.
    BibTeX:
    @article{McFarland2001,
      author = {McFarland, K and Kalivas, PW},
      title = {The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2001},
      volume = {21},
      number = {21},
      pages = {8655-8663}
    }
    
    McFarland, K., Lapish, C. & Kalivas, P. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior {2003} JOURNAL OF NEUROSCIENCE
    Vol. {23}({8}), pp. {3531-3537} 
    article  
    Abstract: The relative contributions of glutamate and dopamine within the nucleus accumbens to cocaine-induced reinstatement of drug-seeking behavior were assessed. When extinguished cocaine self-administration behavior was reinstated by a cocaine-priming injection, extracellular levels of both dopamine and glutamate were elevated in the nucleus accumbens. However, when yoked cocaine or saline control subjects were administered a cocaine prime, only dopamine levels were elevated. Thus, glutamate increased only when animals reinstated lever pressing, whereas dopamine increased regardless of behavior. The increase in glutamate was not accounted for simply by the act of lever pressing itself, because the cocaine self-administration group still demonstrated elevated glutamate when the levers were withdrawn from the operant chamber. Moreover, reinstatement of lever pressing for food did not elevate extracellular glutamate, indicating that increased glutamate initiated responding selectively for a drug reinforcement. The source of glutamate was shown to be glutamatergic afferents from the prefrontal cortex because inhibiting prefrontal cortical glutamatergic neurons that project to the accumbens prevented the rise in glutamate. Together, these data demonstrate that activation of a glutamatergic projection from the prefrontal cortex to the nucleus accumbens underlies cocaine-primed reinstatement of drug-seeking behavior.
    BibTeX:
    @article{McFarland2003,
      author = {McFarland, K and Lapish, CC and Kalivas, PW},
      title = {Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2003},
      volume = {23},
      number = {8},
      pages = {3531-3537}
    }
    
    McGaugh, J. The amygdala modulates the consolidation of memories of emotionally arousing experiences {2004} ANNUAL REVIEW OF NEUROSCIENCE
    Vol. {27}, pp. {1-28} 
    article DOI  
    Abstract: Converging findings of animal and human studies provide compelling evidence that the amygdala is critically involved in enabling us to acquire and retain lasting memories of emotional experiences. This review focuses primarily on the findings of research investigating the role of the amygdala in modulating the consolidation of long-term memories. Considerable evidence from animal studies investigating the effects of posttraining systemic or intra-amygdala infusions of hormones and drugs, as well as selective lesions of specific amygdala nuclei, indicates that (a) the amygdala mediates the memory-modulating effects of adrenal stress hormones and several classes of neurotransmitters; (b) the effects are selectively mediated by the basolateral complex of the amygdala (BLA); (c) the influences involve interactions of several neuromodulatory systems within the BLA that converge in influencing noradrenergic and muscarinic cholinergic activation; (d) the BLA modulates memory consolidation via efferents to other brain regions, including the caudate nucleus, nucleus accumbens, and cortex; and (e) the BLA modulates the consolidation of memory of many different kinds of information. The findings of human brain imaging studies are consistent with those of animal studies in suggesting that activation of the amygdala influences the consolidation of long-term memory; the degree of activation of the amygdala by emotional arousal during encoding of emotionally arousing material (either pleasant or unpleasant) correlates highly with subsequent recall. The activation of neuromodulatory systems affecting the BLA and its projections to other brain regions involved in processing different kinds of information plays a key role in enabling emotionally significant experiences to be well remembered.
    BibTeX:
    @article{McGaugh2004,
      author = {McGaugh, JL},
      title = {The amygdala modulates the consolidation of memories of emotionally arousing experiences},
      journal = {ANNUAL REVIEW OF NEUROSCIENCE},
      year = {2004},
      volume = {27},
      pages = {1-28},
      doi = {{10.1146/annurev.neuro.27.070203.144157}}
    }
    
    MEADORWOODRUFF, J., MANSOUR, A., HEALY, D., KUEHN, R., ZHOU, Q., BUNZOW, J., AKIL, H., CIVELLI, O. & WATSON, S. COMPARISON OF THE DISTRIBUTIONS OF D1 AND D2 DOPAMINE RECEPTOR MESSENGER-RNAS IN RAT-BRAIN {1991} NEUROPSYCHOPHARMACOLOGY
    Vol. {5}({4}), pp. {231-242} 
    article  
    Abstract: The distributions of messenger RNAs encoding both the D1 and D2 dopamine receptors have been determined in the rat brain by in situ hybridization. High levels of both mRNAs were found in the traditional dopaminoceptive regions of brain, including the caudate-putamen, nucleus accumbens, and olfactory tubercle; lower levels of both were found in a number of other neural structures, such as the lateral septum, olfactory bulb, hypothalamus, and cortex. High levels of D2 but not D1 receptor mRNA were identified in the midbrain dopamine cell groups, suggesting that the autoreceptors found in the substantia nigra and ventral tegmental area are exclusively D2. Other areas demonstrating differential distribution of these two mRNAs included the pituitary, amygdala, and hippocampus. Quantitative densitometric analysis revealed that in most of the brain regions studied in which both messages exist, the amounts of D1 and D2 receptor mRNAs were approximately equal. Finally, using thin (2.5-mu-m) sections through the caudate-putamen, about half of all cells were found to be positive for D1 receptor mRNA, and approximately 75% of cells contained D2 receptor mRNA. Subsequent analysis in sequential sections revealed that co-localization of D1 and D2 receptor mRNA occurred in 33% +/- 7% of all caudate-putamen cells: about half of all cells containing D1 receptor mRNA also contained D2 receptor mRNA, and approximately half of all D2 receptor mRNA-positive cells also contained D1 receptor mRNA. These results indicate that there is considerable overlap between D1 and D2 dopaminoceptive cells, and provide a basis for future regulatory studies of dopamine systems in brain within a defined anatomic context.
    BibTeX:
    @article{MEADORWOODRUFF1991,
      author = {MEADORWOODRUFF, JH and MANSOUR, A and HEALY, DJ and KUEHN, R and ZHOU, QY and BUNZOW, JR and AKIL, H and CIVELLI, O and WATSON, SJ},
      title = {COMPARISON OF THE DISTRIBUTIONS OF D1 AND D2 DOPAMINE RECEPTOR MESSENGER-RNAS IN RAT-BRAIN},
      journal = {NEUROPSYCHOPHARMACOLOGY},
      year = {1991},
      volume = {5},
      number = {4},
      pages = {231-242}
    }
    
    Meck, W. Neuropharmacology of timing and time perception {1996} COGNITIVE BRAIN RESEARCH
    Vol. {3}({3-4}), pp. {227-242} 
    article  
    Abstract: Time is a guiding force in the behavior of all organisms. For both a rat in an experimental setting (e.g. Skinner box) trying to predict when reinforcement will be delivered and a human in a restaurant waiting for his dinner to be served an accurate perception of time is an important determinant of behavior. Recent research has used a combination of pharmacological and behavioral manipulations to gain a fuller understanding of how temporal information is processed. A psychological model of duration discrimination that differentiates the speed of an internal clock used for the registration of current sensory input from the speed of the memory-storage process used for the representation of the durations of prior stimulus events has proven useful in integrating these findings. Current pharmacological research suggests that different stages of temporal processing may involve separate brain regions and be modified by different neurotransmitter systems. For example, the internal clock used to time durations in the seconds-to-minutes range appears linked to dopamine (DA) function in the basal ganglia, while temporal memory and attentional mechanisms appear linked to acetylcholine (ACh) function in the frontal cortex. These two systems are connected by frontal-striatal loops, thus allowing for the completion of the timing sequences involved in duration discrimination.
    BibTeX:
    @article{Meck1996,
      author = {Meck, WH},
      title = {Neuropharmacology of timing and time perception},
      journal = {COGNITIVE BRAIN RESEARCH},
      year = {1996},
      volume = {3},
      number = {3-4},
      pages = {227-242}
    }
    
    Meil, W. & See, R. Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine {1997} BEHAVIOURAL BRAIN RESEARCH
    Vol. {87}({2}), pp. {139-148} 
    article  
    Abstract: This study investigated the ability of bilateral excitotoxic lesions of the basolateral amygdala (BLA) to disrupt cocaine self-administration, responding during extinction sessions, and stimulus cued recovery of extinguished responding in rats. BLA and sham lesions following 7 days of 3 h limited access cocaine self-administration sessions (0.33 mg/infusion) on a fixed ratio I (FR1) schedule of reinforcement failed to alter cocaine intake and responding on 7 subsequent days of self-administration. This lack of effect suggests that the BLA is not paramount for the maintenance of cocaine's reinforcing effects. In contrast, BLA lesions, but not sham lesions, following 7 or 14 days of cocaine self-administration attenuated responding on a lever associated with cocaine infusions on the first day of extinction sessions and blocked the ability of drug associated stimuli to reinstate extinguished responding following 20 daily extinction sessions. However, lesions of the BLA did not attenuate stimulus cued recovery of responding following 43 days of withdrawal. These results are consistent with the hypothesis that the BLA is important for the conditioned incentive properties of reinforcers, but not primary reinforcement itself. (C) 1997 Elsevier Science B.V.
    BibTeX:
    @article{Meil1997,
      author = {Meil, WM and See, RE},
      title = {Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {1997},
      volume = {87},
      number = {2},
      pages = {139-148}
    }
    
    MELIS, M. & ARGIOLAS, A. DOPAMINE AND SEXUAL-BEHAVIOR {1995} NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
    Vol. {19}({1}), pp. {19-38} 
    article  
    Abstract: Among central neurotransmitters involved in the control of sexual behavior; dopamine is certainly one of the most extensively studied. Our attempt to review old and recent neuropharmacological, biochemical, electrophysiological, and psychobiological studies performed so far only in rats, monkeys, and humans, provides evidence that dopamine through its different neuronal systems and receptor subtypes plays different roles in the control of several aspects of sexual behavior. In fact, while the nigrostriatal system is necessary for the control of the sensory-motor coordination required for copulation, the mesolimbic-mesocortical system plays a key role in the preparatory phase of the behavior, mainly in sexual arousal, motivation and possibly reward. Conversely, the incertohypothalamic system plays a major role in the consummation of the behavior, mainly in seminal emission and erectile performance, but evidence for its involvement in sexual motivation also exists. The dopaminergic receptors playing the major rob in the control of male sexual behavior belong to the D-2 receptor subtype. However a D-1/D-2 receptor interaction is well established and an opposite role for D-1 and D-2 receptors in the preoptic area suggested. Despite some differences, most studies show that treatments that increase or decrease, respectively, brain dopaminergic activity improve or worsen, respectively, several parameters of copulatory activity, supporting a facilitatory role of dopamine in male sexual behavior. In contrast, no conclusion can be deduced from the available studies on the role of central dopaminergic systems in the control of proceptivity and receptivity, the two main components of female sexual behavior.
    BibTeX:
    @article{MELIS1995,
      author = {MELIS, MR and ARGIOLAS, A},
      title = {DOPAMINE AND SEXUAL-BEHAVIOR},
      journal = {NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS},
      year = {1995},
      volume = {19},
      number = {1},
      pages = {19-38}
    }
    
    Mello, N. & Negus, S. Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures {1996} NEUROPSYCHOPHARMACOLOGY
    Vol. {14}({6}), pp. {375-424} 
    article  
    Abstract: Drug abuse is a major public health problem, and the relationship between intravenous drug abuse and AIDS underscores the need for more effective treatment medications. Animal models of drug self-administration are useful to systematically evaluate new treatment medications and predict clinical efficacy. This review summarizes the status of preclinical evaluations of medications for treatment of cocaine and opiate abuse. The basic drug self-administration methodology and the rationale for experimental designs and outcome criteria are described. Studies of the effects of dopamine or opioid receptor agonists and antagonists as well as medications used clinically for other indications on drug self-administration are critically examined. Where possible, the degree of concordance between clinical and preclinical studies of drug abuse treatment medications is discussed. We conclude that drug self-administration models are valuable for preclinical assessment of medication efficacy, and we recommend some strategies to further improve evaluation procedures. The discovery of more effective medications for substance abuse treatment should be facilitated by recent advances in behavioral science, pharmacology, neurobiology and medicinal chemistry.
    BibTeX:
    @article{Mello1996,
      author = {Mello, NK and Negus, SS},
      title = {Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures},
      journal = {NEUROPSYCHOPHARMACOLOGY},
      year = {1996},
      volume = {14},
      number = {6},
      pages = {375-424}
    }
    
    Meltzer, H., Li, Z., Kaneda, Y. & Ichikawa, J. Serotonin receptors : their key role in drugs to treat schizophrenia {2003} PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
    Vol. {27}({7}), pp. {1159-1172} 
    article DOI  
    Abstract: Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D-2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drag when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative ``fast-off'' hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the ``slow'' off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D-3 or D-4 receptor, and drugs that are selective for them. (C) 2003 Published by Elsevier Inc.
    BibTeX:
    @article{Meltzer2003,
      author = {Meltzer, HY and Li, Z and Kaneda, Y and Ichikawa, J},
      title = {Serotonin receptors : their key role in drugs to treat schizophrenia},
      journal = {PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY},
      year = {2003},
      volume = {27},
      number = {7},
      pages = {1159-1172},
      doi = {{10.1016/j.pnpbp.2003.09.010}}
    }
    
    MELTZER, H. & NASH, J. EFFECTS OF ANTIPSYCHOTIC-DRUGS ON SEROTONIN RECEPTORS .7. {1991} PHARMACOLOGICAL REVIEWS
    Vol. {43}({4}), pp. {587-604} 
    article  
    BibTeX:
    @article{MELTZER1991,
      author = {MELTZER, HY and NASH, JF},
      title = {EFFECTS OF ANTIPSYCHOTIC-DRUGS ON SEROTONIN RECEPTORS .7.},
      journal = {PHARMACOLOGICAL REVIEWS},
      year = {1991},
      volume = {43},
      number = {4},
      pages = {587-604},
      note = {CONF ON SEROTONIN AND NEUROPSYCHIATRIC DISORDERS : IMPLICATIONS FOR THE DISCOVERY OF NEW PSYCHOTHERAPEUTIC AGENTS, HERSHEY, PA, OCT 03, 1990}
    }
    
    Miller, G., Gainetdinov, R., Levey, A. & Caron, M. Dopamine transporters and neuronal injury {1999} TRENDS IN PHARMACOLOGICAL SCIENCES
    Vol. {20}({10}), pp. {424-429} 
    article  
    Abstract: The plasma membrane dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2) are essential for normal dopamine neurotransmission. DAT terminates the actions of dopamine by rapidly removing dopamine from the synapse, whereas VMAT2 loads cytoplasmic dopamine into vesicles for storage and subsequent release. Recent data suggest that perturbation of the tightly regulated balance between these two transporters predisposes the neurone to damage by a variety of insults. Most notable is the selective degeneration of DAT- and VMAT2-expressing dopamine nerve terminals in the striatum thought to underlie Parkinson's disease. DAT and VMAT2 expression can predict the selective vulnerability of neuronal populations, which suggests that therapeutic strategies aimed at altering DAT and VMAT2 function could have significant benefits in a variety of disorders.
    BibTeX:
    @article{Miller1999,
      author = {Miller, GW and Gainetdinov, RR and Levey, AI and Caron, MG},
      title = {Dopamine transporters and neuronal injury},
      journal = {TRENDS IN PHARMACOLOGICAL SCIENCES},
      year = {1999},
      volume = {20},
      number = {10},
      pages = {424-429}
    }
    
    Mirenowicz, J. & Schultz, W. Preferential activation of midbrain dopamine neurons by appetitive rather than aversive stimuli {1996} NATURE
    Vol. {379}({6564}), pp. {449-451} 
    article  
    Abstract: MIDBRAIN dopamine systems are crucially involved in motivational processes underlying the learning and execution of goal-directed behaviour(1-5). Dopamine neurons in monkeys are uniformly activated by unpredicted appetitive stimuli such as food and liquid rewards and conditioned, reward-predicting stimuli. By contrast, fully predicted stimuli are ineffective(6-8), and the omission of predicted reward depresses their activity(9). These characteristics follow associative-learning rules(10,11), suggesting that dopamine responses report an error in reward prediction(12). Accordingly, neural network models are efficiently trained using a dopamine-like reinforcement signal(13,14). However, it is unknown whether the responses to environmental stimuli concern specific motivational attributes or reflect more general stimulus salience(4,15). To resolve this, we have compared dopamine impulse responses to motivationally opposing appetitive and aversive stimuli. In contrast to appetitive events, primary and conditioned non-noxious aversive stimuli either failed to activate dopamine neurons or, in cases of close resemblance with appetitive stimuli, induced weaker responses than appetitive stimuli. Thus, dopamine neurons preferentially report environmental stimuli with appetitive rather than aversive motivational value.
    BibTeX:
    @article{Mirenowicz1996,
      author = {Mirenowicz, J and Schultz, W},
      title = {Preferential activation of midbrain dopamine neurons by appetitive rather than aversive stimuli},
      journal = {NATURE},
      year = {1996},
      volume = {379},
      number = {6564},
      pages = {449-451}
    }
    
    MOGA, M., WEIS, R. & MOORE, R. EFFERENT PROJECTIONS OF THE PARAVENTRICULAR THALAMIC NUCLEUS IN THE RAT {1995} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {359}({2}), pp. {221-238} 
    article  
    Abstract: The paraventricular nucleus of the thalamus (PVT) receives input from all major components of the circadian timing system, including the suprachiasmatic nucleus (SCN), the intergeniculate leaflet and the retina. For a better understanding of the role of this nucleus in circadian timing, we examined the distribution of its efferent projections using the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L). The efferent projections of the PVT are loosely organized along its dorsal-ventral and anterior-posterior axes. The anterior PVT sends projections to the SCN; the dorsomedial and ventromedial hypothalamic nuclei; the lateral septum; the bed nucleus of the stria terminalis; the central and basomedial amygdaloid nuclei; the anterior olfactory nucleus; the olfactory tubercle; the nucleus accumbens; the infralimbic, piriform, and perirhinal cortices; the ventral subiculum; and the endopiriform nucleus. A small PHA-L injection, restricted to the ventral portion of the anterior PVT, produces a similar pattern of labeling, except for a marked decrease in the number of labeled fibers in the hypothalamus, cortex, and lateral septum and an increase in labeling in the endopiriform nucleus and basolateral amygdaloid nucleus. The posterior PVT has a more limited efferent distribution than the anterior PVT, terminating in the anterior olfactory nucleus; the olfactory tubercle; the nucleus accumbens; and the central, basolateral, and basomedial nuclei of the amygdala. Our results show that the anterior PVT is ideally situated to relay circadian timing information from the SCN to brain areas involved in visceral and motivational aspects of behavior and to provide feedback regulation of the SCN. (C) 1995 Wiley-Liss, Inc.
    BibTeX:
    @article{MOGA1995,
      author = {MOGA, MM and WEIS, RP and MOORE, RY},
      title = {EFFERENT PROJECTIONS OF THE PARAVENTRICULAR THALAMIC NUCLEUS IN THE RAT},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1995},
      volume = {359},
      number = {2},
      pages = {221-238}
    }
    
    MOGENSON, G., SWANSON, L. & WU, M. NEURAL PROJECTIONS FROM NUCLEUS ACCUMBENS TO GLOBUS PALLIDUS, SUBSTANTIA INNOMINATA, AND LATERAL PREOPTIC-LATERAL HYPOTHALAMIC AREA - AN ANATOMICAL AND ELECTRO-PHYSIOLOGICAL INVESTIGATION IN THE RAT {1983} JOURNAL OF NEUROSCIENCE
    Vol. {3}({1}), pp. {189-202} 
    article  
    BibTeX:
    @article{MOGENSON1983,
      author = {MOGENSON, GJ and SWANSON, LW and WU, M},
      title = {NEURAL PROJECTIONS FROM NUCLEUS ACCUMBENS TO GLOBUS PALLIDUS, SUBSTANTIA INNOMINATA, AND LATERAL PREOPTIC-LATERAL HYPOTHALAMIC AREA - AN ANATOMICAL AND ELECTRO-PHYSIOLOGICAL INVESTIGATION IN THE RAT},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1983},
      volume = {3},
      number = {1},
      pages = {189-202}
    }
    
    MOGHADDAM, B. STRESS PREFERENTIALLY INCREASES EXTRANEURONAL LEVELS OF EXCITATORY AMINO-ACIDS IN THE PREFRONTAL CORTEX - COMPARISON TO HIPPOCAMPUS AND BASAL GANGLIA {1993} JOURNAL OF NEUROCHEMISTRY
    Vol. {60}({5}), pp. {1650-1657} 
    article  
    Abstract: The technique of intracerebral microdialysis was used to assess the effect of stress on the extracellular concentrations of excitatory amino acids, glutamate and aspartate, in the rat medial prefrontal cortex, hippocampus, striatum, and nucleus accumbens. A 20-min restraint procedure led to an increase in extracellular glutamate in all regions tested. The increase in glutamate levels was significantly higher in the prefrontal cortex than that observed in other regions. With the exception of the striatum, extracellular levels of aspartate were increased in all regions. Furthermore, the increase in aspartate levels was significantly higher in prefrontal cortex compared to hippocampus and nucleus accumbens. Local perfusion of tetrodotoxin during the restraint procedure significantly decreased the stress-induced increase in extracellular excitatory amino acids. In order to ensure that the above results were not an artifact of restraint not associated with stress (e.g., decreased mobility), we also examined the effect of swimming stress on the extracellular levels of excitatory amino acids in selected regions, i.e., striatum and medial prefrontal cortex. Both regions displayed a significant increase in extracellular levels of aspartate and glutamate following 20 min of swimming in room temperature water. This study provides direct evidence that stress increases the neuronal release of excitatory amino acids in a regionally selective manner. The implications of the present findings for stress-induced catecholamine release and/or hippocampal degeneration are discussed.
    BibTeX:
    @article{MOGHADDAM1993,
      author = {MOGHADDAM, B},
      title = {STRESS PREFERENTIALLY INCREASES EXTRANEURONAL LEVELS OF EXCITATORY AMINO-ACIDS IN THE PREFRONTAL CORTEX - COMPARISON TO HIPPOCAMPUS AND BASAL GANGLIA},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1993},
      volume = {60},
      number = {5},
      pages = {1650-1657}
    }
    
    Moghaddam, B., Adams, B., Verma, A. & Daly, D. Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex {1997} JOURNAL OF NEUROSCIENCE
    Vol. {17}({8}), pp. {2921-2927} 
    article  
    Abstract: Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal robe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.
    BibTeX:
    @article{Moghaddam1997,
      author = {Moghaddam, B and Adams, B and Verma, A and Daly, D},
      title = {Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1997},
      volume = {17},
      number = {8},
      pages = {2921-2927}
    }
    
    MOGHADDAM, B. & BUNNEY, B. ACUTE EFFECTS OF TYPICAL AND ATYPICAL ANTIPSYCHOTIC-DRUGS ON THE RELEASE OF DOPAMINE FROM PREFRONTAL CORTEX, NUCLEUS-ACCUMBENS, AND STRIATUM OF THE RAT - AN INVIVO MICRODIALYSIS STUDY {1990} JOURNAL OF NEUROCHEMISTRY
    Vol. {54}({5}), pp. {1755-1760} 
    article  
    BibTeX:
    @article{MOGHADDAM1990,
      author = {MOGHADDAM, B and BUNNEY, BS},
      title = {ACUTE EFFECTS OF TYPICAL AND ATYPICAL ANTIPSYCHOTIC-DRUGS ON THE RELEASE OF DOPAMINE FROM PREFRONTAL CORTEX, NUCLEUS-ACCUMBENS, AND STRIATUM OF THE RAT - AN INVIVO MICRODIALYSIS STUDY},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1990},
      volume = {54},
      number = {5},
      pages = {1755-1760}
    }
    
    Mohn, A., Gainetdinov, R., Caron, M. & Koller, B. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia {1999} CELL
    Vol. {98}({4}), pp. {427-436} 
    article  
    Abstract: N-methyl-D-aspartate receptors (NMDARs) represent a subclass of glutamate receptors that play a critical role in neuronal development and physiology. We report here the generation of mice expressing only 5% of normal levels of the essential NMDAR1 (NR1) subunit. Unlike NR1 null mice, these mice survive to adulthood and display behavioral abnormalities, including increased motor activity and stereotypy and deficits in social and sexual interactions. These behavioral alterations are similar to those observed in pharmacologically induced animal models of schizophrenia and can be ameliorated by treatment with haloperidol or clozapine, antipsychotic drugs that antagonize dopaminergic and serotonergic receptors. These findings support a model in which reduced NMDA receptor activity results in schizophrenic-like behavior and reveals how pharmacological manipulation of monoaminergic pathways can affect this phenotype.
    BibTeX:
    @article{Mohn1999,
      author = {Mohn, AR and Gainetdinov, RR and Caron, MG and Koller, BH},
      title = {Mice with reduced NMDA receptor expression display behaviors related to schizophrenia},
      journal = {CELL},
      year = {1999},
      volume = {98},
      number = {4},
      pages = {427-436}
    }
    
    MORATALLA, R., ROBERTSON, H. & GRAYBIEL, A. DYNAMIC REGULATION OF NGFI-A (ZIF268, EGR1) GENE-EXPRESSION IN THE STRIATUM {1992} JOURNAL OF NEUROSCIENCE
    Vol. {12}({7}), pp. {2609-2622} 
    article  
    Abstract: The expression of immediate-early genes of the fos/jun leucine zipper family can be regulated in striatal neurons by stimuli affecting the dopaminergic nigrostriatal system. The regulatory effects are gene specific, region specific, and striatal compartment specific. In the experiments reported here, we have explored the possibility that dopaminergic stimulation might also affect striatal expression of NGFI-A, a member of the zinc finger family of immediate-early genes. We treated healthy adult rats with amphetamine or cocaine and monitored the acute response of striatal neurons by in situ hybridization with oligonucleotide probes for NGFI-A mRNA. Both drugs evoked rapid, anatomically patterned increases in NGFI-A mRNA expression in the dorsal striatum (caudoputamen) and in the ventral striatum (nucleus accumbens, olfactory tubercle). The main response to each drug was in medium-sized neurons, known to be the projection neurons of the striatum. At every dose of amphetamine eliciting a response, the increased NGFI-A mRNA expression was preferentially concentrated in striosomes of the rostral caudoputamen, whereas cocaine at each dose given induced expression of NGFI-A mRNA in both striosomes and matrix at these striatal levels. The two indirect agonists evoked NGFI-A expression in both striatal compartments farther caudally, especially in the central and medial caudoputamen. Activation by both drugs was blocked by pretreatment with the D1-selective dopamine receptor antagonist SCH23390. These patterns of NGFI-A activation are remarkably similar to those found for Fos-like immunoreactivity following acute amphetamine and cocaine treatments, Suggesting that coordinate activation of members of at least two immediate-early gene families occurs in the striatum following catecholaminergic stimulation. Such patterns of induction strongly support the view that the genomic responsiveness of the striosome and of the matrix compartments of the rostral striatum are distinct at the level of early-response gene expression. These findings raise the interesting possibility that some of the well-known effects of dopaminergic stimulation on neuropeptide and neurotransmitter expression in the striatum may reflect particular combinatorial patterns of immediate-early gene activation.
    BibTeX:
    @article{MORATALLA1992,
      author = {MORATALLA, R and ROBERTSON, HA and GRAYBIEL, AM},
      title = {DYNAMIC REGULATION OF NGFI-A (ZIF268, EGR1) GENE-EXPRESSION IN THE STRIATUM},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1992},
      volume = {12},
      number = {7},
      pages = {2609-2622}
    }
    
    Moron, J., Brockington, A., Wise, R., Rocha, B. & Hope, B. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: Evidence from knock-out mouse lines {2002} JOURNAL OF NEUROSCIENCE
    Vol. {22}({2}), pp. {389-395} 
    article  
    Abstract: Selective blockers of the norepinephrine transporter (NET) inhibit dopamine uptake in the prefrontal cortex. This suggests that dopamine in this region is normally cleared by the somewhat promiscuous NET We have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of H-3-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice. At transporter-specific concentrations, nisoxetine and GBR12909 failed to block dopamine uptake into frontal cortex synaptosomes from NET knock-out mice. The efficacy of cocaine at the highest dose (1 mm) was normal in DAT knock-out mice but reduced by 70% in NET knock-out mice. Nisoxetine inhibited dopamine uptake by 20% in caudate and nucleus accumbens synaptosomes from wild-type and DAT knock-out mice but had no effect in those from NET knock-out mice. Cocaine failed to block dopamine uptake into caudate or nucleus accumbens synaptosomes from DAT knock-out mice. Cocaine and GBR12909 each inhibited dopamine uptake into caudate synaptosomes from NET knock-out mice, but cocaine effectiveness was reduced in the case of nucleus accumbens synaptosomes. Thus, whereas dopamine uptake in caudate and nucleus accumbens depends primarily on the DAT, dopamine uptake in frontal cortex depends primarily on the NET. These data underscore the fact that which transporter clears dopamine from a given region depends on both the affinities and the local densities of the transporters.
    BibTeX:
    @article{Moron2002,
      author = {Moron, JA and Brockington, A and Wise, RA and Rocha, BA and Hope, BT},
      title = {Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: Evidence from knock-out mouse lines},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2002},
      volume = {22},
      number = {2},
      pages = {389-395}
    }
    
    MURASE, S., GRENHOFF, J., CHOUVET, G., GONON, F. & SVENSSON, T. PREFRONTAL CORTEX REGULATES BURST FIRING AND TRANSMITTER RELEASE IN RAT MESOLIMBIC DOPAMINE NEURONS STUDIED IN-VIVO {1993} NEUROSCIENCE LETTERS
    Vol. {157}({1}), pp. {53-56} 
    article  
    Abstract: The influence of the medial prefrontal cortex (PFC) on mesolimbic dopamine activity was studied with electrophysiological techniques and in vivo voltammetry in the chloral hydrate-anesthetized male rat. Glutamate injected into the PFC selectively increased burst firing of single dopamine cells in the ventral tegmental area and enhanced the release of dopamine from nerve terminals in the nucleus accumbens. PFC injection of the local anesthetic lidocaine produced the opposite effects on burst firing and terminal release. This selective modulation of the dynamic activity of mesolimbic dopamine neurons by the prefrontal cortex might be important in motivation, learning and schizophrenia.
    BibTeX:
    @article{MURASE1993,
      author = {MURASE, S and GRENHOFF, J and CHOUVET, G and GONON, FG and SVENSSON, TH},
      title = {PREFRONTAL CORTEX REGULATES BURST FIRING AND TRANSMITTER RELEASE IN RAT MESOLIMBIC DOPAMINE NEURONS STUDIED IN-VIVO},
      journal = {NEUROSCIENCE LETTERS},
      year = {1993},
      volume = {157},
      number = {1},
      pages = {53-56}
    }
    
    MURRAY, A., RYOO, H., GUREVICH, E. & JOYCE, J. LOCALIZATION OF DOPAMINE D-3 RECEPTORS TO MESOLIMBIC AND D-2 RECEPTORS TO MESOSTRIATAL REGIONS OF HUMAN FOREBRAIN {1994} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {91}({23}), pp. {11271-11275} 
    article  
    Abstract: We characterized the binding of [I-125]epidepride to dopamine D-2-like and D-3-like receptors in tissue sections of human striatum. The competition for binding of [I-125]epidepride by domperidone, quinpirole, and 7-hydroxy-N,N-di(1-propyl)-2-aminotetralin (7-OH-DPAT) was best fit by assuming one site in the caudate but two sites in nucleus accumbens. Guanosine 5'-[beta,gamma-imido]triphosphate showed a large modulatory influence in agonist inhibition of [I-125]epidepride binding in caudate but not in nucleus accumbens. The binding of [I-125]epidepride in the presence of 7-OH-DPAT (1000-fold selective for D-3-like versus D-2-like sites) and domperidone (20-fold selective for D-2-like versus D-3-like sites) was used to quantify the numbers of D-2-like and D-3-like receptors in areas of human brain. The distribution of D-2-like and D-3-like receptors was largely nonoverlapping. Binding of [I-125]epidepride to D-3-like receptors was negligible in the dorsal striatum but was concentrated in islands of dense binding in the nucleus accumbens and ventral putamen that aligned with acetylcho linesterase-poor striosomes. Binding to D-3-like receptors was also enriched in the internal globus pallidus, ventral pallidum, septum, islands of Calleja, nucleus basalis, amygdalostriatal transition nucleus of the amygdala, central nucleus of the amygdala, and ventral tegmental area. Binding of [I-125]epidepride to D-2 but not D-3 receptors was detected in cortex and hippocampus.
    BibTeX:
    @article{MURRAY1994,
      author = {MURRAY, AM and RYOO, HL and GUREVICH, E and JOYCE, JN},
      title = {LOCALIZATION OF DOPAMINE D-3 RECEPTORS TO MESOLIMBIC AND D-2 RECEPTORS TO MESOSTRIATAL REGIONS OF HUMAN FOREBRAIN},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1994},
      volume = {91},
      number = {23},
      pages = {11271-11275}
    }
    
    NAKAYA, Y., KANEKO, T., SHIGEMOTO, R., NAKANISHI, S. & MIZUNO, N. IMMUNOHISTOCHEMICAL LOCALIZATION OF SUBSTANCE-P RECEPTOR IN THE CENTRAL-NERVOUS-SYSTEM OF THE ADULT-RAT {1994} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {347}({2}), pp. {249-274} 
    article  
    Abstract: In an attempt to reveal the function sites of substance P (SP) in the central nervous system (CNS), the distribution of SP receptor (SPR) was immunocytochemically investigated in adult rat and compared with that of SP-positive fibers. SPR-like immunoreactivity (LI) was mostly localized to neuronal cell bodies and dendrites. Neurons with intense SPR-LI were distributed densely in the cortical amygdaloid nucleus, hilus of the dentate gyrus, locus ceruleus, rostral half of the ambiguus nucleus, and intermediolateral nucleus of the thoracic cord; moderately in the caudatoputamen, nucleus accumbens, olfactory tubercle, median, pontine, and magnus raphe nuclei, laminae I and III of the caudal subnucleus of the spinal trigeminal nucleus, and lamina I of the spinal cord; and sparsely in the cerebral cortex, basal nucleus of Meynert, claustrum, gigantocellular reticular nucleus, and lobules IX and X of the cerebellar vermis. Neurons with weak to moderate SPR-LI were distributed more widely throughout the CNS. The regional patterns of distribution of SPR-LI were not necessarily the same as those of SP-positive fibers. The entopeduncular nucleus, substantia nigra, and lateral part of the interpeduncular nucleus showed intense SP-LI but displayed almost no SPR-LI. Conversely, the hilus of the dentate gyrus, anterodorsal thalamic nucleus, central nucleus of the inferior colliculus, and dorsal tegmental nucleus showed intense to moderate SPR-LI but contained few axons with SP-LI. These findings confirmed the presence of the `'mismatch'' problem between SP and SPR localizations. However, the distribution of SPR-LI was quite consistent with that of the SP-binding activity, which has been studied via autoradiography. This indicates that the sites of SPR-LI revealed in the present study represent most, if not all, sites of SP-binding activity. (C) 1994 Wiley-Liss, Inc.
    BibTeX:
    @article{NAKAYA1994,
      author = {NAKAYA, Y and KANEKO, T and SHIGEMOTO, R and NAKANISHI, S and MIZUNO, N},
      title = {IMMUNOHISTOCHEMICAL LOCALIZATION OF SUBSTANCE-P RECEPTOR IN THE CENTRAL-NERVOUS-SYSTEM OF THE ADULT-RAT},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1994},
      volume = {347},
      number = {2},
      pages = {249-274}
    }
    
    NAUTA, W., SMITH, G., FAULL, R. & DOMESICK, V. EFFERENT CONNECTIONS AND NIGRAL AFFERENTS OF NUCLEUS ACCUMBENS SEPTI IN RAT {1978} NEUROSCIENCE
    Vol. {3}({4-5}), pp. {385-401} 
    article  
    BibTeX:
    @article{NAUTA1978,
      author = {NAUTA, WJH and SMITH, GP and FAULL, RLM and DOMESICK, VB},
      title = {EFFERENT CONNECTIONS AND NIGRAL AFFERENTS OF NUCLEUS ACCUMBENS SEPTI IN RAT},
      journal = {NEUROSCIENCE},
      year = {1978},
      volume = {3},
      number = {4-5},
      pages = {385-401}
    }
    
    Neisewander, J., Baker, D., Fuchs, R., Tran-Nguyen, L., Palmer, A. & Marshall, J. Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment {2000} JOURNAL OF NEUROSCIENCE
    Vol. {20}({2}), pp. {798-805} 
    article  
    Abstract: To examine neuronal activation associated with incentive motivation for cocaine, cocaine-seeking behavior (operant responding without cocaine reinforcement) and Fos expression were examined in rats exposed to saline and cocaine priming injections and/or a self-administration environment. Rats were first trained to self-administer cocaine or received yoked saline administration (''control''). They then received 21 daily exposures to either the self-administration environment (''extinction'') or a different environment (''no extinction'') without cocaine available. Extinction training, used to decrease incentive motivation for cocaine elicited by the self-administration environment, decreased cocaine-seeking behavior elicited by both the environment and the cocaine priming injection. Exposure to the self-administration environment enhanced Fos expression in the no extinction group relative to control and extinction groups in the anterior cingulate, basolateral amygdala, hippocampal CA1 region, dentate gyrus, nucleus accumbens shell and core, and central gray area, regardless of whether or not priming injections were given. The priming injections enhanced Fos expression in the ventral tegmental area, caudate putamen, substantia nigra pars reticulata, entorhinal cortex, central amygdala, lateral amygdala, arcuate nucleus, and central gray area, regardless of group. Thus, these changes likely reflect an unconditioned effect from either cocaine or injection stress. The priming injections also enhanced Fos expression in the anterior cingulate, but only in cocaine-experienced groups, suggesting that this enhancement reflects an experience-dependent motivational effect of the priming injections. The results suggest that different neural circuits may be involved in the incentive motivational effects of cocaine-paired environmental stimuli versus priming injections and that the anterior cingulate may be part of a common pathway for both.
    BibTeX:
    @article{Neisewander2000,
      author = {Neisewander, JL and Baker, DA and Fuchs, RA and Tran-Nguyen, LTL and Palmer, A and Marshall, JF},
      title = {Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2000},
      volume = {20},
      number = {2},
      pages = {798-805}
    }
    
    Nestler, E. Is there a common molecular pathway for addiction? {2005} NATURE NEUROSCIENCE
    Vol. {8}({11}), pp. {1445-1449} 
    article DOI  
    Abstract: Drugs of abuse have very different acute mechanisms of action but converge on the brain's reward pathways by producing a series of common functional effects after both acute and chronic administration. Some similar actions occur for natural rewards as well. Researchers are making progress in understanding the molecular and cellular basis of these common effects. A major goal for future research is to determine whether such common underpinnings of addiction can be exploited for the development of more effective treatments for a wide range of addictive disorders.
    BibTeX:
    @article{Nestler2005,
      author = {Nestler, EJ},
      title = {Is there a common molecular pathway for addiction?},
      journal = {NATURE NEUROSCIENCE},
      year = {2005},
      volume = {8},
      number = {11},
      pages = {1445-1449},
      doi = {{10.1038/nn1578}}
    }
    
    Nestler, E. Molecular basis of long-term plasticity underlying addiction {2001} NATURE REVIEWS NEUROSCIENCE
    Vol. {2}({2}), pp. {119-128} 
    article  
    Abstract: Studies of human addicts and behavioural studies in rodent models of addiction indicate that key behavioural abnormalities associated with addiction are extremely long lived. So, chronic drug exposure causes stable changes in the brain at the molecular and cellular levels that underlie these behavioural abnormalities. There has been considerable progress in identifying the mechanisms that contribute to long-lived neural and behavioural plasticity related to addiction, including drug-induced changes in gene transcription, in RNA and protein processing, and in synaptic structure. Although the specific changes identified so far are not sufficiently long lasting to account for the nearly permanent changes in behaviour associated with addiction, recent work has pointed to the types of mechanism that could be involved.
    BibTeX:
    @article{Nestler2001,
      author = {Nestler, EJ},
      title = {Molecular basis of long-term plasticity underlying addiction},
      journal = {NATURE REVIEWS NEUROSCIENCE},
      year = {2001},
      volume = {2},
      number = {2},
      pages = {119-128}
    }
    
    Nestler, E. & Aghajanian, G. Molecular and cellular basis of addiction {1997} SCIENCE
    Vol. {278}({5335}), pp. {58-63} 
    article  
    Abstract: Drug addiction results from adaptations in specific brain neurons caused by repeated exposure to a drug of abuse. These adaptations combine to produce the complex behaviors that define an addicted slate. Progress is being made in identifying such time-dependent, drug-induced adaptations and relating them to specific behavioral features of addiction. Current research needs to understand the types of adaptations that underlie the particularly long-lived aspects of addiction, such as drug craving and relapse, and to identify specific genes that contribute to individual differences in vulnerability to addiction. Understanding the molecular and cellular basis of addictive states will lead to major changes in how addiction is viewed and ultimately treated.
    BibTeX:
    @article{Nestler1997,
      author = {Nestler, EJ and Aghajanian, GK},
      title = {Molecular and cellular basis of addiction},
      journal = {SCIENCE},
      year = {1997},
      volume = {278},
      number = {5335},
      pages = {58-63}
    }
    
    Nestler, E., Barrot, M., DiLeone, R., Eisch, A., Gold, S. & Monteggia, L. Neurobiology of depression {2002} NEURON
    Vol. {34}({1}), pp. {13-25} 
    article  
    Abstract: Current treatments for depression are inadequate for many individuals, and progress in understanding the neurobiology of depression is slow. Several promising hypotheses of depression and antidepressant action have been formulated recently. These hypotheses are based largely on dysregulation of the hypothalamic-pituitary-adrenal axis and hippocampus and implicate corticotropin-releasing factor, glucocorticoids, brain-derived neurotrophic factor, and CREB. Recent work has looked beyond hippocampus to other brain areas that are also likely involved. For example, nucleus accumbens, amygdala, and certain hypothalamic nuclei are critical in regulating motivation, eating, sleeping, energy level, circadian rhythm, and responses to rewarding and aversive stimuli, which are all abnormal in depressed patients. A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome. These advances will fundamentally improve the treatment and prevention of depression.
    BibTeX:
    @article{Nestler2002,
      author = {Nestler, EJ and Barrot, M and DiLeone, RJ and Eisch, AJ and Gold, SJ and Monteggia, LM},
      title = {Neurobiology of depression},
      journal = {NEURON},
      year = {2002},
      volume = {34},
      number = {1},
      pages = {13-25}
    }
    
    Nestler, E., Barrot, M. & Self, D. Delta FosB: A sustained molecular switch for addiction {2001} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {98}({20}), pp. {11042-11046} 
    article  
    Abstract: The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor Delta FosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. Delta FosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of Delta FosB occurs after compulsive running, which suggests that Delta FosB may accumulate in response to many types of compulsive behaviors. Importantly, Delta FosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, Delta FosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either Delta FosB or a dominant negative inhibitor of the protein provide direct evidence that Delta FosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that Delta FosB functions as a type of sustained ``molecular switch'' that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.
    BibTeX:
    @article{Nestler2001a,
      author = {Nestler, EJ and Barrot, M and Self, DW},
      title = {Delta FosB: A sustained molecular switch for addiction},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {2001},
      volume = {98},
      number = {20},
      pages = {11042-11046}
    }
    
    Nestler, E. & Carlezon, W. The mesolimbic dopamine reward circuit in depression {2006} BIOLOGICAL PSYCHIATRY
    Vol. {59}({12}), pp. {1151-1159} 
    article DOI  
    Abstract: The neural circuitry that mediates mood under normal and abnormal conditions remains incompletely understood. Most attention in the field has focused on hippocampal and frontal cortical regions for their role in depression and antidepressant action. While these regions no doubt play important roles in these phenomena, there is compelling evidence that other brain regions are also involved. Here we focus on the potential role of the nucleus accumbens (NAc; ventral striatum) and its dopaminergic input from the ventral tegmental area (VTA), which form the mesolimbic dopamine system, in depression. The mesolimbic dopamine system is most often associated with the rewarding effects of food, sex, and drugs of abuse. Given the prominence of anhedonia, reduced motivation, and decreased energy level in most individuals with depression, we propose that the NAc and VTA contribute importantly to the pathophysiology and symptomatology of depression and may even be involved in its etiology. We review recent studies showing that manipulations of key proteins (e.g. CREB, dynorphin, BDNF, MCH, or Clock) within the VTA-NAc circuit of rodents produce unique behavioral phenotypes, some of which are directly relevant to depression. Studies of these and other proteins in the mesolimbic dopamine system have established novel approaches to modeling key symptoms of depression in animals, and could enable the development of antidepressant medications with fundamentally new mechanisms of action.
    BibTeX:
    @article{Nestler2006,
      author = {Nestler, EJ and Carlezon, WA},
      title = {The mesolimbic dopamine reward circuit in depression},
      journal = {BIOLOGICAL PSYCHIATRY},
      year = {2006},
      volume = {59},
      number = {12},
      pages = {1151-1159},
      doi = {{10.1016/j.biopsych.2005.09.018}}
    }
    
    NESTLER, E., HOPE, B. & WIDNELL, K. DRUG-ADDICTION - A MODEL FOR THE MOLECULAR-BASIS OF NEURAL PLASTICITY {1993} NEURON
    Vol. {11}({6}), pp. {995-1006} 
    article  
    BibTeX:
    @article{NESTLER1993,
      author = {NESTLER, EJ and HOPE, BT and WIDNELL, KL},
      title = {DRUG-ADDICTION - A MODEL FOR THE MOLECULAR-BASIS OF NEURAL PLASTICITY},
      journal = {NEURON},
      year = {1993},
      volume = {11},
      number = {6},
      pages = {995-1006}
    }
    
    NGUYEN, T., KOSOFSKY, B., BIRNBAUM, R., COHEN, B. & HYMAN, S. DIFFERENTIAL EXPRESSION OF C-FOS AND ZIF268 IN RAT STRIATUM AFTER HALOPERIDOL, CLOZAPINE, AND AMPHETAMINE {1992} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {89}({10}), pp. {4270-4274} 
    article  
    Abstract: Antipsychotic drugs are monoamine receptor antagonists. However, the mechanisms by which these direct actions are translated into therapeutic effects are unknown. Candidate mechanisms include receptor-mediated regulation of gene expression in target neurons. Inducible transcription factors, including certain immediate early genes (IEGs), may mediate between receptor-activated second messenger systems and expression of genes involved in the differentiated functions of neurons. We examined the specificity of induction of the IEGs c-fos and zif268 after acute administration of several antipsychotic drugs and, for comparison, the stimulant amphetamine, which has pharmacologic effects relatively opposite to those of antipsychotics. Antipsychotic drugs with potent dopamine D2 receptor antagonist properties, such as haloperidol, induced both c-fos and zif268 mRNA in the caudate-putamen; however, the atypical antipsychotic drug clozapine induced zif268 but not c-fos mRNA in that region. Similarly, haloperidol, but not clozapine, induced c-Fos-like immunoreactivity in the caudate-putamen. In contrast, both drugs induced c-Fos-like immunoreactivity in the nucleus accumbens. Like haloperidol, amphetamine induced both c-fos and zif268 mRNA in the caudate-putamen, but the anatomic patterns of induction of c-Fos-like immunoreactivity by the two drugs were dramatically different. Haloperidol and amphetamine induced AP-1 binding activity in cell extracts from the caudate-putamen, indicating that drug-induced IEG expression results in protein products that may function in the regulation of target gene expression. Thus these data demonstrate that inductions of IEG expression by haloperidol, clozapine, and amphetamine are specific, may be biologically relevant, and suggest avenues for further investigation.
    BibTeX:
    @article{NGUYEN1992,
      author = {NGUYEN, TV and KOSOFSKY, BE and BIRNBAUM, R and COHEN, BM and HYMAN, SE},
      title = {DIFFERENTIAL EXPRESSION OF C-FOS AND ZIF268 IN RAT STRIATUM AFTER HALOPERIDOL, CLOZAPINE, AND AMPHETAMINE},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1992},
      volume = {89},
      number = {10},
      pages = {4270-4274}
    }
    
    Nicola, S., Surmeier, D. & Malenka, R. Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens {2000} ANNUAL REVIEW OF NEUROSCIENCE
    Vol. {23}, pp. {185-215} 
    article  
    Abstract: The striatum and its ventral extension, the nucleus accumbens, are involved in behaviors as diverse as motor planning, drug seeking, and learning. Invariably, these striatally mediated behaviors depend on intact dopaminergic innervation. However, the mechanisms by which dopamine modulates neuronal function in the striatum and nucleus accumbens have been difficult to elucidate. Recent electrophysiological studies have revealed that dopamine alters both voltage-dependent conductances and synaptic transmission, resulting in state-dependent modulation of target cells. These studies make clear predictions about how dopamine, particularly via D-1 receptor activation, should alter the responsiveness of striatal neurons to extrinsic excitatory synaptic activity.
    BibTeX:
    @article{Nicola2000,
      author = {Nicola, SM and Surmeier, DT and Malenka, RC},
      title = {Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens},
      journal = {ANNUAL REVIEW OF NEUROSCIENCE},
      year = {2000},
      volume = {23},
      pages = {185-215}
    }
    
    NISELL, M., NOMIKOS, G. & SVENSSON, T. SYSTEMIC NICOTINE-INDUCED DOPAMINE RELEASE IN THE RAT NUCLEUS-ACCUMBENS IS REGULATED BY NICOTINIC RECEPTORS IN THE VENTRAL TEGMENTAL AREA {1994} SYNAPSE
    Vol. {16}({1}), pp. {36-44} 
    article  
    Abstract: Stimulation of the mesolimbic dopamine (DA) system is considered of major importance for the rewarding and dependence producing properties of nicotine (NIC). To identify the site of this stimulatory action, simultaneous microdialysis was performed in the ventral tegmental area (VTA) and the ipsilateral nucleus accumbens (NAC) of awake rats. Extracellular concentrations of DA and its metabolites were measured in the NAC. NIC (0.5 mg/kg, s.c.) increased DA and its metabolites by similar to 50 Concomitant infusion of the nicotinic receptor antagonist mecamylamine (MEC, 100 mu M) through the VTA probe, starting 40 min before NIC injection, antagonized the NIC induced increases of DA and its metabolites. In contrast, similar MEC pretreatment (40 or 140 min) in the NAC did not affect DA or metabolite responses to systemic NIC. Infusion of NIC (1,000 mu M) in the NAC or the VTA increased DA release by 49% and 48 respectively, whereas only the VTA infusion increased metabolite concentrations by similar to 25 MEC infusion (1-1,000 mu M) in the VTA did not affect DA or its metabolites, whereas the 1,000 mu M concentration infused in the NAC increased DA by 77 These results suggest that nicotinic receptors in the somatodendritic region may be of greater importance than those located in the terminal area for the stimulatory action of systemic NIC on the mesolimbic DA system. Furthermore, our findings support the notion that the mesolimbic dopaminergic system is phasically rather than tonically regulated by nicotinic receptor activation within the VTA. (C) 1994 Wiley-Liss, Inc.
    BibTeX:
    @article{NISELL1994,
      author = {NISELL, M and NOMIKOS, GG and SVENSSON, TH},
      title = {SYSTEMIC NICOTINE-INDUCED DOPAMINE RELEASE IN THE RAT NUCLEUS-ACCUMBENS IS REGULATED BY NICOTINIC RECEPTORS IN THE VENTRAL TEGMENTAL AREA},
      journal = {SYNAPSE},
      year = {1994},
      volume = {16},
      number = {1},
      pages = {36-44}
    }
    
    NOBLE, E., BLUM, K., RITCHIE, T., MONTGOMERY, A. & SHERIDAN, P. ALLELIC ASSOCIATION OF THE D2 DOPAMINE RECEPTOR GENE WITH RECEPTOR-BINDING CHARACTERISTICS IN ALCOHOLISM {1991} ARCHIVES OF GENERAL PSYCHIATRY
    Vol. {48}({7}), pp. {648-654} 
    article  
    Abstract: The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and nonalcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease TaqI and probed with a 1.5-kilobase (kb) digest of a clone (lambda-hD2G1) of the human D2 dopamine receptor gene. The binding characteristics (K(d) [binding affinity] and B(max) [number of binding sites]) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted K(d) was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the Al allele, in whom a high association with alcoholism was found, the B(max) was significantly reduced compared with the B(max) of subjects with the A2 allele. Moreover, a progressively reduced B(max) was found in subjects with A2/A2, Al/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.
    BibTeX:
    @article{NOBLE1991,
      author = {NOBLE, EP and BLUM, K and RITCHIE, T and MONTGOMERY, A and SHERIDAN, PJ},
      title = {ALLELIC ASSOCIATION OF THE D2 DOPAMINE RECEPTOR GENE WITH RECEPTOR-BINDING CHARACTERISTICS IN ALCOHOLISM},
      journal = {ARCHIVES OF GENERAL PSYCHIATRY},
      year = {1991},
      volume = {48},
      number = {7},
      pages = {648-654}
    }
    
    O'Brien, C., Childress, A., Ehrman, R. & Robbins, S. Conditioning factors in drug abuse: can they explain compulsion? {1998} JOURNAL OF PSYCHOPHARMACOLOGY
    Vol. {12}({1}), pp. {15-22} 
    article  
    Abstract: There is a good deal of clinical evidence suggesting that compulsion to resume drug taking is an important part of the addiction syndrome. The symptoms comprising motivation to resume drug use, namely craving and compulsion, have been studied experimentally in human subjects. While much work remains to be done, there is evidence showing that these symptoms are influenced by learning. The research has been guided by animal studies demonstrating that drug effects can be conditioned. Much attention has been directed toward demonstrating the existence of drug conditioning in human addicts and exploring the neurological structures that may underlie such learned responses,We do not yet know the relative importance of learning in the overall phenomenon of relapse, and treatments based on conditioning principles are still under investigation.
    BibTeX:
    @article{O'Brien1998,
      author = {O'Brien, CP and Childress, AR and Ehrman, R and Robbins, SJ},
      title = {Conditioning factors in drug abuse: can they explain compulsion?},
      journal = {JOURNAL OF PSYCHOPHARMACOLOGY},
      year = {1998},
      volume = {12},
      number = {1},
      pages = {15-22}
    }
    
    ODONNELL, P. & GRACE, A. SYNAPTIC-INTERACTIONS AMONG EXCITATORY AFFERENTS TO NUCLEUS-ACCUMBENS NEURONS - HIPPOCAMPAL GATING OF PREFRONTAL CORTICAL INPUT {1995} JOURNAL OF NEUROSCIENCE
    Vol. {15}({5, Part 1}), pp. {3622-3639} 
    article  
    Abstract: The interactions among excitatory inputs arising from the prefrontal cortex, amygdala, and hippocampus, and innervating nucleus accumbens neurons were studied using in vivo intracellular recording techniques. Neurons recorded in the accumbens displayed one of three activity states: (1) silent, (2) spontaneously firing at low, constant rates, or (3) a bistable membrane potential, characterized by alternating periods of activity and silence occurring in concert with spontaneous transitions between two steady-state membrane potentials (average, -77.3 +/- 7.1 mV base, -63.0 +/- 7.4 mV plateau). These neurons also exhibited a high degree of convergence of responses elicited by stimulation of each of the three excitatory inputs tested. Activation of hippocampal afferents, but not cortical, amygdaloid, or thalamic afferents, induced bistable cells to switch to the depolarized (active) state. In contrast, no bistable cells were encountered in the nucleus accumbens following an acute transection of the fornix. Furthermore, microinjection of lidocaine in the vicinity of the hippocampal afferents at the level of the fornix caused a reversible elimination of the plateau phase in bistable cells. These data suggest that hippocampal input is necessary for accumbens neurons to enter a depolarized, active state, Furthermore, activation of prefrontal cortical inputs fail to evoke spike firing in accumbens neurons unless they are in this active state. Consequently, the hippocampus appears to be capable of gating prefrontal corticoaccumbens throughput.
    BibTeX:
    @article{ODONNELL1995,
      author = {ODONNELL, P and GRACE, AA},
      title = {SYNAPTIC-INTERACTIONS AMONG EXCITATORY AFFERENTS TO NUCLEUS-ACCUMBENS NEURONS - HIPPOCAMPAL GATING OF PREFRONTAL CORTICAL INPUT},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1995},
      volume = {15},
      number = {5, Part 1},
      pages = {3622-3639}
    }
    
    OHISHI, H., SHIGEMOTO, R., NAKANISHI, S. & MIZUNO, N. DISTRIBUTION OF THE MESSENGER-RNA FOR A METABOTROPIC GLUTAMATE-RECEPTOR (MGLUR3) IN THE RAT-BRAIN - AN IN-SITU HYBRIDIZATION STUDY {1993} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {335}({2}), pp. {252-266} 
    article  
    Abstract: Distribution of the mRNA for a metabotropic glutamate receptor, mGluR3, which is coupled to the inhibitory cAMP cascade, was examined in the central nervous system of the adult albino rat by in situ hybridization. The hybridization signals of mGluR3 were detected not only on neuronal cells but also on many glial cells throughout the brain and spinal cord. In the neuronal cells, prominent expression of mGluR3 mRNA was seen in the thalamic reticular nucleus. Moderately labeled neurons were seen in the anterior olfactory nucleus, cerebral neo- and mesocortical regions, lateral amygdaloid nucleus, ventral part of the basolateral amygdaloid nucleus, dorsal endopiriform nucleus, supraoptic nucleus, superficial layers of the superior colliculus, inferior colliculus, interpeduncular nucleus, superior olivary nuclei, and Golgi cells in the cerebellar cortex. Weakly labeled neurons were observed in the striatum, nucleus accumbens, ventral pallidum, globus pallidus, entopeduncular nucleus, lateral hypothalamic area, hypothalamic paraventricular nucleus, medial habenular nucleus, anterior pretectal nucleus, Barrington's nucleus, Nucleus O, paragenual nucleus, trigeminal sensory complex, cochlear nuclei, dorsal motor nucleus of the trigeminal nerve, dorsal cap of the inferior olive, spinal dorsal horn, and lamina X of the spinal cord. The stellate cells in the cerebellar cortex, and neurons in the deep cerebellar nuclei were also labeled weakly. The granule cell layer of the dentate gyrus, as a whole, appeared to be labeled intensely, but each of the granule cells was labeled only weakly. No significant labeling was detected in the mitral and tufted cells in the olfactory bulb, hippocampal pyramidal cells, Purkinje and granule cells in the cerebellar cortex, or somatic motoneurons. The distribution of mGluR3 mRNA in particular neurons and glial cells indicates specific roles of mGluR3 in the glutamatergic system of the central nervous system. (C) 1993 Wiley-Liss, Inc.
    BibTeX:
    @article{OHISHI1993,
      author = {OHISHI, H and SHIGEMOTO, R and NAKANISHI, S and MIZUNO, N},
      title = {DISTRIBUTION OF THE MESSENGER-RNA FOR A METABOTROPIC GLUTAMATE-RECEPTOR (MGLUR3) IN THE RAT-BRAIN - AN IN-SITU HYBRIDIZATION STUDY},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1993},
      volume = {335},
      number = {2},
      pages = {252-266}
    }
    
    OLDS, M. REINFORCING EFFECTS OF MORPHINE IN THE NUCLEUS ACCUMBENS {1982} BRAIN RESEARCH
    Vol. {237}({2}), pp. {429-440} 
    article  
    BibTeX:
    @article{OLDS1982,
      author = {OLDS, ME},
      title = {REINFORCING EFFECTS OF MORPHINE IN THE NUCLEUS ACCUMBENS},
      journal = {BRAIN RESEARCH},
      year = {1982},
      volume = {237},
      number = {2},
      pages = {429-440}
    }
    
    Ongur, D. & Price, J. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans {2000} CEREBRAL CORTEX
    Vol. {10}({3}), pp. {206-219} 
    article  
    Abstract: This paper reviews architectonic subdivisions and connections of the orbital and medial prefrontal cortex (OMPFC) in rats, monkeys and humans. Cortico-cortical connections provide the basis for recognition of `medial' and `orbital' networks within the OMPFC. These networks also have distinct connections with structures in other parts of the brain. The orbital network receives sensory inputs from several modalities, including olfaction, taste, visceral afferents, somatic sensation and vision, which appear to be especially related to food or eating. In contrast, the medial network provides the major cortical output to visceromotor structures in the hypothalamus and brainstem. The two networks have distinct connections with areas of the striatum and mediodorsal thalamus. In particular, projections to the nucleus accumbens and the adjacent ventromedial caudate and putamen arise predominantly from the medial network. Both networks also have extensive connections with limbic structures. Based on these and other observations, the OMPFC appears to function as a sensory-visceromotor link, especially for eating. This linkage appears to he critical for the guidance of reward-related behavior and for setting of mood. Imaging and histological observations on human brains indicate that clinical depressive disorders are associated with specific functional and cellular changes in the OMPFC, including activity and volume changes, and specific changes in the number of glial cells.
    BibTeX:
    @article{Ongur2000,
      author = {Ongur, D and Price, JL},
      title = {The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans},
      journal = {CEREBRAL CORTEX},
      year = {2000},
      volume = {10},
      number = {3},
      pages = {206-219}
    }
    
    PAKKENBERG, B. PRONOUNCED REDUCTION OF TOTAL NEURON NUMBER IN MEDIODORSAL THALAMIC NUCLEUS AND NUCLEUS-ACCUMBENS IN SCHIZOPHRENICS {1990} ARCHIVES OF GENERAL PSYCHIATRY
    Vol. {47}({11}), pp. {1023-1028} 
    article  
    BibTeX:
    @article{PAKKENBERG1990,
      author = {PAKKENBERG, B},
      title = {PRONOUNCED REDUCTION OF TOTAL NEURON NUMBER IN MEDIODORSAL THALAMIC NUCLEUS AND NUCLEUS-ACCUMBENS IN SCHIZOPHRENICS},
      journal = {ARCHIVES OF GENERAL PSYCHIATRY},
      year = {1990},
      volume = {47},
      number = {11},
      pages = {1023-1028}
    }
    
    Parkinson, J., Olmstead, M., Burns, L., Robbins, T. & Everitt, B. Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive Pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-Amphetamine {1999} JOURNAL OF NEUROSCIENCE
    Vol. {19}({6}), pp. {2401-2411} 
    article  
    Abstract: Dopamine release within the nucleus accumbens (NAcc) has been associated with both the rewarding and locomotor-stimulant effects of abused drugs. The functions of the NAcc core and shell were investigated in mediating amphetamine-potentiated conditioned reinforcement and locomotion. Rats were initially trained to associate a neutral stimulus (Pavlovian CS) with food reinforcement (US). After excitotoxic lesions that selectively destroyed either the NAcc core or shell, animals underwent additional CS-US training sessions and then were tested for the acquisition of a new instrumental response that produced the CS acting as a conditioned reinforcer (CR). Animals were infused intra-NAcc with D-amphetamine (0, 1, 3, 10, or 20 mu g) before each session. Shell lesions affected neither Pavlovian nor instrumental conditioning but completely abolished the potentiative effect of intra-NAcc amphetamine on responding with CR. Core-lesioned animals were impaired during the Pavlovian retraining sessions but showed no deficit in the acquisition of responding with CR. However, the selectivity in stimulant-induced potentiation of the CR lever was reduced, as intra-NAcc amphetamine infusions dose-dependently increased responding on both the CR lever and a nonreinforced (control) lever. Shell lesions produced hypoactivity and attenuated amphetamine-induced activity. In contrast, core lesions resulted in hyperactivity and enhanced the locomotor-stimulating effect of amphetamine. These results indicate a functional dissociation of subregions of the NAcc; the shell is a critical site for stimulant effects underlying the enhancement of responding with CR and locomotion after intra-NAcc injections of amphetamine, whereas the core is implicated in mechanisms underlying the expression of CS-US associations.
    BibTeX:
    @article{Parkinson1999,
      author = {Parkinson, JA and Olmstead, MC and Burns, LH and Robbins, TW and Everitt, BJ},
      title = {Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive Pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-Amphetamine},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1999},
      volume = {19},
      number = {6},
      pages = {2401-2411}
    }
    
    PARSONS, L. & JUSTICE, J. PERFUSATE SEROTONIN INCREASES EXTRACELLULAR DOPAMINE IN THE NUCLEUS-ACCUMBENS AS MEASURED BY INVIVO MICRODIALYSIS {1993} BRAIN RESEARCH
    Vol. {606}({2}), pp. {195-199} 
    article  
    Abstract: The effects of local application of serotonin (5-HT) on extracellular levels of dopamine (DA) in the nucleus accumbens (N. ACC) were assessed using in vivo microdialysis. At a perfusate flow rate of 0.3 mul/min the baseline dialysate concentration of DA was 2.1 +/- 0.7 nM (mean +/- S.E.M.; n = 5) and significantly increased to 142 +/- 18 220 +/- 47% and 332 +/- 35% of baseline when 0.1 muM, 0.2 muM and 0.4 muM concentrations of 5-HT were included in the perfusate. Perfusate 5-HT concentrations below 0.1 muM had no effect on dialysate DA. The in vivo dialysis efficiency for 5-HT was found to be 39 +/- 12 and thus the concentrations of 5-HT reaching the extracellular space at the surface of the dialysis membrane were estimated to be 40,80 and 160 nM for the 0.1, 0.2 and 0.4 muM 5-HT perfusates, respectively. The serotonin-induced increase in dialysate DA was attenuated by co-perfusion of 0.4 muM 5-HT with 4 muM concentrations of pindolol (a relatively non-specific 5-HT1 antagonist; 151 +/- 7% vs. 332 +/- 35% baseline dialysate DA for 5-HT/antagonist and 5-HT-only perfusates, respectively), LY 53,857 (a specific 5-HT2 antagonist; 130 +/- 17% vs. 332 +/- 35 and MDL 7222 (a specific 5-HT3 antagonist; 143 +/- 19% vs. 332 +/- 35. While the contributions of the 5-HT, receptor subtype are unclear, the inhibitory efficacy of a highly specific 5-HT2 antagonist and-an antagonist specific to 5-HT2 and 5-HT3 receptors suggest that both of these receptor subtypes are involved in the serotonin-induced DA increase in the N. ACC.
    BibTeX:
    @article{PARSONS1993,
      author = {PARSONS, LH and JUSTICE, JB},
      title = {PERFUSATE SEROTONIN INCREASES EXTRACELLULAR DOPAMINE IN THE NUCLEUS-ACCUMBENS AS MEASURED BY INVIVO MICRODIALYSIS},
      journal = {BRAIN RESEARCH},
      year = {1993},
      volume = {606},
      number = {2},
      pages = {195-199}
    }
    
    PARSONS, L. & JUSTICE, J. EXTRACELLULAR CONCENTRATION AND INVIVO RECOVERY OF DOPAMINE IN THE NUCLEUS-ACCUMBENS USING MICRODIALYSIS {1992} JOURNAL OF NEUROCHEMISTRY
    Vol. {58}({1}), pp. {212-218} 
    article  
    Abstract: The present study compared two different in vivo microdialysis methods which estimate the extracellular concentration of analytes at a steady state where there is no effect of probe sampling efficiency. Each method was used to estimate the basal extracellular concentration of dopamine (DA) in the nucleus accumbens of the rat. In the first method, DA is added to the perfusate at concentrations above and below the expected extracellular concentration (0, 2.5, 5, and 10 nM) and DA is measured in the dialysate from the brain to generate a series of points which are interpolated to determine the concentration of no net flux. Using this method, basal DA was estimated to be 4.2 +/- 0.2 nM (mean +/- SEM, n = 5). The slope of the regression gives the in vivo recovery of DA, which was 65 +/- 5 This method was also used to estimate a basal extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) concentration in the nucleus accumbens of 5.7 +/- 0.6-mu-M, with an in vivo recovery of 52 +/- 11% (n = 5). A further experiment which extended the perfusate concentration range showed that the in vivo recovery of DA is significantly higher than the in vivo recovery of DOPAC (p < 0.001), whereas the in vitro recoveries of DA and DOPAC are not significantly different from each other. The in vivo difference is thought to be caused by active processes associated with the DA nerve terminal, principally release and uptake of DA, which may alter the concentration gradient in the tissue surrounding the probe. The second method measures dialysate DA at several perfusion flow rates (0.1, 0.2, 0.4, and 1.2-mu-l/min) and extrapolates the data to zero flow using a nonlinear least squares regression. This method estimated a basal extracellular DA concentration of 3.9 +/- 0.2 nM (n = 5). The two independent methods are in reasonable agreement that the extracellular concentration of DA in the nucleus accumbens is about 4 nM.
    BibTeX:
    @article{PARSONS1992,
      author = {PARSONS, LH and JUSTICE, JB},
      title = {EXTRACELLULAR CONCENTRATION AND INVIVO RECOVERY OF DOPAMINE IN THE NUCLEUS-ACCUMBENS USING MICRODIALYSIS},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1992},
      volume = {58},
      number = {1},
      pages = {212-218}
    }
    
    PARSONS, L., SMITH, A. & JUSTICE, J. BASAL EXTRACELLULAR DOPAMINE IS DECREASED IN THE RAT NUCLEUS-ACCUMBENS DURING ABSTINENCE FROM CHRONIC COCAINE {1991} SYNAPSE
    Vol. {9}({1}), pp. {60-65} 
    article  
    Abstract: Rats were treated for 10 days with cocaine (20 mg/kg, i.p.) followed by either 1 or 10 days of abstinence. On the test day a microdialysis method was performed in which dopamine (DA) was added to the perfusate at concentrations above and below the expected extracellular concentration (0, 2.5, 5, and 10 nM) to generate a series of points that can be interpolated to determine the concentration of no net flux, which represents the extracellular DA concentration. The slope of the line generated by this method is the in vivo recovery of the dialysis probe. After 1 day of abstinence, there was no significant difference in basal DA levels in the nucleus accumbens (N ACC) between cocaine treated (4.1 +/- 0.3 nM; mean +/- SEM) and saline-treated (3.9 +/- 0.2 nM) groups. However, there was a significant increase in the slope of the cocaine-treated group (0.91 +/- 0.04 vs. 0.67 +/- 0.08; P > 0.03). After 10 days of abstinence, there were reduced basal extracellular levels of DA in the N ACC of the cocaine-treated group as compared with saline-treated controls (P < 0.002). The basal extracellular DA concentration in the N ACC was 2.1 +/- 0.3 nM for the cocaine group and 3.9 +/- 0.2 nM for the control group. The slopes of the curves were not significantly different for the cocaine (0.63 +/- 0.07) and saline (0.64 +/- 0.09) groups. There was a significant interaction between cocaine and the length of abstinence with respect to the reduction in basal extracellular DA in the N ACC (P < 0.0008) and also an interaction between cocaine and the length of abstinence with respect to the slope of the regression lines (P < 0.03). The results suggest that both basal levels and the dynamics of extracellular DA in the N ACC are altered by chronic cocaine. These alterations may have relevance to the dopamine depletion hypothesis of cocaine addiction.
    BibTeX:
    @article{PARSONS1991,
      author = {PARSONS, LH and SMITH, AD and JUSTICE, JB},
      title = {BASAL EXTRACELLULAR DOPAMINE IS DECREASED IN THE RAT NUCLEUS-ACCUMBENS DURING ABSTINENCE FROM CHRONIC COCAINE},
      journal = {SYNAPSE},
      year = {1991},
      volume = {9},
      number = {1},
      pages = {60-65}
    }
    
    PAULSON, P., CAMP, D. & ROBINSON, T. TIME COURSE OF TRANSIENT BEHAVIORAL DEPRESSION AND PERSISTENT BEHAVIORAL SENSITIZATION IN RELATION TO REGIONAL BRAIN MONOAMINE CONCENTRATIONS DURING AMPHETAMINE WITHDRAWAL IN RATS {1991} PSYCHOPHARMACOLOGY
    Vol. {103}({4}), pp. {480-492} 
    article  
    Abstract: This experiment was designed to characterize the withdrawal syndrome produced by discontinuation of treatment with escalating, non-neurotoxic doses of d-amphetamine (AMPH). AMPH withdrawal was associated with both transient and persistent changes in behavior and postmortem brain tissue catecholamine concentrations. During the first week of withdrawal rats showed a significant decrease in spontaneous nocturnal locomotor activity. This behavioral depression was most pronounced on the first 2 days after the discontinuation of AMPH pretreatment, was still evident after 1 week, but had dissipated by 4 weeks. Behavioral depression was not due to a simple motor deficit, because AMPH-pretreated animals showed a normal large increase in locomotion when the lights initially went out, but they did not sustain relatively high levels of locomotor activity throughout the night, or show the early morning rise in activity characteristic of controls. Behavioral depression was associated with a transient decrease in the concentration of norepinephrine (NE) in the hypothalamus, and a transient decrease in the ability of an AMPH challenge to alter dopamine (DA) concentrations in the caudate-putamen and nucleus accumbens. AMPH pretreatment also produced persistent changes in brain and behavior. The persistent effects of AMPH were not evident in spontaneous locomotor activity, but were revealed by a subsequent challenge injection of AMPH. AMPH pretreated animals were markedly hyper-responsive to the stereotypy-producing effects of an AMPH challenge. This behavioral sensitization was not fully developed until 2 weeks after the discontinuation of AMPH pretreatment, but then persisted undiminished for at least 1 year. It is suggested that the transient changes in brain and behavior described here may represent an animal analogue of the ``distress syndrome'' seen in humans during AMPH withdrawal, which is associated with symptoms of depression and alterations in catecholamine function. On the other hand, persistent behavioral sensitization may be analogous to the enduring hypersensitivity to the psychotogenic effects of AMPH seen in former AMPH addicts.
    BibTeX:
    @article{PAULSON1991,
      author = {PAULSON, PE and CAMP, DM and ROBINSON, TE},
      title = {TIME COURSE OF TRANSIENT BEHAVIORAL DEPRESSION AND PERSISTENT BEHAVIORAL SENSITIZATION IN RELATION TO REGIONAL BRAIN MONOAMINE CONCENTRATIONS DURING AMPHETAMINE WITHDRAWAL IN RATS},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1991},
      volume = {103},
      number = {4},
      pages = {480-492}
    }
    
    PAULSON, P. & ROBINSON, T. AMPHETAMINE-INDUCED TIME-DEPENDENT SENSITIZATION OF DOPAMINE NEUROTRANSMISSION IN THE DORSAL AND VENTRAL STRIATUM - A MICRODIALYSIS STUDY IN BEHAVING RATS {1995} SYNAPSE
    Vol. {19}({1}), pp. {56-65} 
    article  
    Abstract: The purpose of this study was to compare the effects of amphetamine exposure on subsequent amphetamine-induced changes in behavior and dopamine (DA) release in the dorsal and ventral striatum, as a function of time following the discontinuation of repeated amphetamine treatment. Rats were pretreated with either saline or an escalating-dose amphetamine regimen, and then received a 0.5 mg/kg amphetamine `'challenge'' after either 3, 7, or 28 days of withdrawal. Animals tested after 28 days of withdrawal were hypersensitive (sensitized) to the locomotor-activating effects of amphetamine, and relative to control animals showed a significant enhancement in amphetamine-stimulated DA release in both the dorsal and ventral striatum, as revealed by in vivo microdialysis. Animals tested after only 3 or 7 days of withdrawal showed neither behavioral sensitization nor enhanced amphetamine-stimulated DA release. These results establish that time-dependent changes in behavioral sensitization to amphetamine are associated with time-dependent changes in amphetamine-stimulated DA release, and support the hypothesis that persistent sensitization-related changes in striatal DA neurotransmission contribute to the expression of behavioral sensitization. (C) 1995 Wiley-Liss, Inc.
    BibTeX:
    @article{PAULSON1995,
      author = {PAULSON, PE and ROBINSON, TE},
      title = {AMPHETAMINE-INDUCED TIME-DEPENDENT SENSITIZATION OF DOPAMINE NEUROTRANSMISSION IN THE DORSAL AND VENTRAL STRIATUM - A MICRODIALYSIS STUDY IN BEHAVING RATS},
      journal = {SYNAPSE},
      year = {1995},
      volume = {19},
      number = {1},
      pages = {56-65}
    }
    
    PENNARTZ, C., DASILVA, F. & GROENEWEGEN, H. THE NUCLEUS-ACCUMBENS AS A COMPLEX OF FUNCTIONALLY DISTINCT NEURONAL ENSEMBLES - AN INTEGRATION OF BEHAVIORAL, ELECTROPHYSIOLOGICAL AND ANATOMICAL DATA {1994} PROGRESS IN NEUROBIOLOGY
    Vol. {42}({6}), pp. {719-\&} 
    article  
    BibTeX:
    @article{PENNARTZ1994,
      author = {PENNARTZ, CMA and DASILVA, FHL and GROENEWEGEN, HJ},
      title = {THE NUCLEUS-ACCUMBENS AS A COMPLEX OF FUNCTIONALLY DISTINCT NEURONAL ENSEMBLES - AN INTEGRATION OF BEHAVIORAL, ELECTROPHYSIOLOGICAL AND ANATOMICAL DATA},
      journal = {PROGRESS IN NEUROBIOLOGY},
      year = {1994},
      volume = {42},
      number = {6},
      pages = {719-&}
    }
    
    PETTIT, H., ETTENBERG, A., BLOOM, F. & KOOB, G. DESTRUCTION OF DOPAMINE IN THE NUCLEUS ACCUMBENS SELECTIVELY ATTENUATES COCAINE BUT NOT HEROIN SELF-ADMINISTRATION IN RATS {1984} PSYCHOPHARMACOLOGY
    Vol. {84}({2}), pp. {167-173} 
    article  
    BibTeX:
    @article{PETTIT1984,
      author = {PETTIT, HO and ETTENBERG, A and BLOOM, FE and KOOB, GF},
      title = {DESTRUCTION OF DOPAMINE IN THE NUCLEUS ACCUMBENS SELECTIVELY ATTENUATES COCAINE BUT NOT HEROIN SELF-ADMINISTRATION IN RATS},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1984},
      volume = {84},
      number = {2},
      pages = {167-173}
    }
    
    PETTIT, H. & JUSTICE, J. DOPAMINE IN THE NUCLEUS ACCUMBENS DURING COCAINE SELF-ADMINISTRATION AS STUDIED BY INVIVO MICRODIALYSIS {1989} PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
    Vol. {34}({4}), pp. {899-904} 
    article  
    BibTeX:
    @article{PETTIT1989,
      author = {PETTIT, HO and JUSTICE, JB},
      title = {DOPAMINE IN THE NUCLEUS ACCUMBENS DURING COCAINE SELF-ADMINISTRATION AS STUDIED BY INVIVO MICRODIALYSIS},
      journal = {PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR},
      year = {1989},
      volume = {34},
      number = {4},
      pages = {899-904}
    }
    
    Phillips, P., Stuber, G., Heien, M., Wightman, R. & Carelli, R. Subsecond dopamine release promotes cocaine seeking {2003} NATURE
    Vol. {422}({6932}), pp. {614-618} 
    article DOI  
    Abstract: The dopamine-containing projection from the ventral tegmental area of the midbrain to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine(1,2). Although neurons in this area respond to rewards on a subsecond timescale(3,4), neurochemical studies have only addressed the role of dopamine in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular dopamine(5-9). To investigate the role of phasic (subsecond) dopamine signalling(10), we measured dopamine every 100 ms in the nucleus accumbens using electrochemical technology(11). Rapid changes in extracellular dopamine concentration were observed at key aspects of drug-taking behaviour in rats. Before lever presses for cocaine, there was an increase in dopamine that coincided with the initiation of drug-seeking behaviours. Notably, these behaviours could be reproduced by electrically evoking dopamine release on this timescale. After lever presses, there were further increases in dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar, rapid dopamine signalling, but only in animals where they had previously been paired to cocaine delivery. These findings reveal an unprecedented role for dopamine in the regulation of drug taking in real time.
    BibTeX:
    @article{Phillips2003,
      author = {Phillips, PEM and Stuber, GD and Heien, MLAV and Wightman, RM and Carelli, RM},
      title = {Subsecond dopamine release promotes cocaine seeking},
      journal = {NATURE},
      year = {2003},
      volume = {422},
      number = {6932},
      pages = {614-618},
      doi = {{10.1038/nature01566}}
    }
    
    PHILLIPSON, O. & GRIFFITHS, A. THE TOPOGRAPHIC ORDER OF INPUTS TO NUCLEUS ACCUMBENS IN THE RAT {1985} NEUROSCIENCE
    Vol. {16}({2}), pp. {275-\&} 
    article  
    BibTeX:
    @article{PHILLIPSON1985,
      author = {PHILLIPSON, OT and GRIFFITHS, AC},
      title = {THE TOPOGRAPHIC ORDER OF INPUTS TO NUCLEUS ACCUMBENS IN THE RAT},
      journal = {NEUROSCIENCE},
      year = {1985},
      volume = {16},
      number = {2},
      pages = {275-&}
    }
    
    Piazza, P. & Le Moal, M. Glucocorticoids as a biological substrate of reward: physiological pathophysiological implications {1997} BRAIN RESEARCH REVIEWS
    Vol. {25}({3}), pp. {359-372} 
    article  
    Abstract: The observations presented in this review suggest that glucocorticoids are one of the biological substrates of reward. These hormones are secreted in response to rewarding stimuli, such as food, a receptive sexual partner or drugs of abuse. Furthermore, manipulations of the secretion of glucocorticoids modify reward-related behaviours, and administration of these hormones, in the range of physiological stress levels, has positive reinforcing effects. The rewarding effects of glucocorticoids are probably mediated by a glucocorticoid-induced stimulation of the mesencephalic dopaminergic transmission, one of the principal neural substrates of reward. It is proposed that the rewarding effects of glucocorticoids play the role of counteracting the aversive effects of external aggressions, allowing a better coping with threatening situations. However, a sustained increase in the secretion of these hormones, or an hypersensitivity to their rewarding effects, could determine reward-related pathologies, such as a predisposed state to develop drug-abuse. In conclusion, through their reward-related effects, glucocorticoids may play a key role in tuning adaptation to stress and in determining reward-related behavioral pathologies. (C) 1997 Elsevier Science B.V.
    BibTeX:
    @article{Piazza1997,
      author = {Piazza, PV and Le Moal, M},
      title = {Glucocorticoids as a biological substrate of reward: physiological pathophysiological implications},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {1997},
      volume = {25},
      number = {3},
      pages = {359-372}
    }
    
    Piazza, P. & LeMoal, M. Pathophysiological basis of vulnerability to drug abuse: Role of an interaction between stress, glucocorticoids, and dopaminergic neurons {1996} ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY
    Vol. {36}, pp. {359-378} 
    article  
    Abstract: Research on drug abuse has recently focused on understanding the vulnerability to develop addiction that is present in certain individuals. These investigations suggest that addiction results from an interaction between drugs and specific individual substrates. Differences in the propensity to develop drug intake can be demonstrated in animals with equal access to drugs under stable laboratory conditions and can be predicted by drug-independent behaviors. Stress, corticosterone, and mesencephalic dopaminergic neurons seem to be organized in a pathophysiological chain determining such a vulnerability. An increased corticosterone secretion, or a higher sensitivity to the effects of this hormone, either naturally present in certain individuals or induced by stress in others, increases the vulnerability to develop drug intake, via an enhancement of the activity of mesencephalic dopaminergic neurons. These findings suggest that addiction therapies should counteract the biological peculiarity that leads some individuals to respond in a pathophysiological way to drugs.
    BibTeX:
    @article{Piazza1996,
      author = {Piazza, PV and LeMoal, M},
      title = {Pathophysiological basis of vulnerability to drug abuse: Role of an interaction between stress, glucocorticoids, and dopaminergic neurons},
      journal = {ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY},
      year = {1996},
      volume = {36},
      pages = {359-378}
    }
    
    PIAZZA, P., ROUGEPONT, F., DEMINIERE, J., KHAROUBI, M., LEMOAL, M. & SIMON, H. DOPAMINERGIC ACTIVITY IS REDUCED IN THE PREFRONTAL CORTEX AND INCREASED IN THE NUCLEUS-ACCUMBENS OF RATS PREDISPOSED TO DEVELOP AMPHETAMINE SELF-ADMINISTRATION {1991} BRAIN RESEARCH
    Vol. {567}({1}), pp. {169-174} 
    article  
    Abstract: Individual vulnerability to the reinforcing effects of drugs appear to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with higher locomotor responses to novelty (High Responders, HR) tend to acquire amphetamine SA, while animals with the lower responses (Low Responders, LR) do not. In this study, we examined whether activity of dopaminergic (DA) and serotoninergic (5-HT) systems differed between HR and LR animals. These transmitter systems are thought to be involved in the reinforcing effects of psychostimulants. Animals from both groups were sacrificed under basal conditions and after exposure for 30 or 120 min to a novel environment, and the DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT, and 5-hydroxyindolacetic acid (5-HIAA) contents were determined in the prefrontal cortex, nucleus accumbens and striatum. The HR rats displayed a specific neurochemical pattern: a higher DOPAC/DA ratio in the nucleus accumbens and striatum and a lower one in the prefrontal cortex. Furthermore, HR animals had lower overall 5-HT and 5-HIAA levels, corresponding to the mean of these compounds for the three structures studied over the three environmental conditions. Since similar DOPAC/DA ratios are found in animals in which the propensity to psychostimulants SA was induced by brain lesions or life events, an opposite pattern of dopaminergic activity in the prefrontal cortex (decrease) and in the ventral and dorsal striatum (increase) may be one of the neurobiological substrate of the predisposition to acquire amphetamine self-administration. The development of this difference may be influenced by interactions between dopaminergic and serotoninergic systems. These results suggest that potential therapeutic strategies for the treatment of addiction will need to take into account the functional heterogeneity of projection systems rather than concentrate on a single neurotransmitter.
    BibTeX:
    @article{PIAZZA1991,
      author = {PIAZZA, PV and ROUGEPONT, F and DEMINIERE, JM and KHAROUBI, M and LEMOAL, M and SIMON, H},
      title = {DOPAMINERGIC ACTIVITY IS REDUCED IN THE PREFRONTAL CORTEX AND INCREASED IN THE NUCLEUS-ACCUMBENS OF RATS PREDISPOSED TO DEVELOP AMPHETAMINE SELF-ADMINISTRATION},
      journal = {BRAIN RESEARCH},
      year = {1991},
      volume = {567},
      number = {1},
      pages = {169-174}
    }
    
    Picciotto, M., Zoli, M., Rimondini, R., Lena, C., Marubio, L., Pich, E., Fuxe, K. & Changeux, J. Acetylcholine receptors containing the beta 2 subunit are involved in the reinforcing properties of nicotine {1998} NATURE
    Vol. {391}({6663}), pp. {173-177} 
    article  
    Abstract: Release of the neurotransmitter dopamine in the mesolimbic system of the brain mediates the reinforcing properties of several drugs of abuse, including nicotine(1). Here we investigate the contribution of the high-affinity neuronal nicotinic acetylcholine receptor(2) to the effects of nicotine on the mesolimbic dopamine system in mice lacking the beta 2 subunit of this receptor(3). We found that nicotine stimulates dopamine release in the ventral striatum of wild-type mice but not in the ventral striatum of beta 2-mutant mice. Using patch-clamp recording, we show that mesencephalic dopaminergic neurons from mice without the beta 2 subunit no longer respond to nicotine, and that self-administration of nicotine is attenuated in these mutant mice. Our results strongly support the idea that the beta 2-containing neuronal nicotinic acetycholine receptor is involv ed in mediating the reinforcing properties of nicotine.
    BibTeX:
    @article{Picciotto1998,
      author = {Picciotto, MR and Zoli, M and Rimondini, R and Lena, C and Marubio, LM and Pich, EM and Fuxe, K and Changeux, JP},
      title = {Acetylcholine receptors containing the beta 2 subunit are involved in the reinforcing properties of nicotine},
      journal = {NATURE},
      year = {1998},
      volume = {391},
      number = {6663},
      pages = {173-177}
    }
    
    Pich, E., Pagliusi, S., Tessari, M., TalabotAyer, D., vanHuijsduijnen, R. & Chiamulera, C. Common neural substrates for the addictive properties of nicotine and cocaine {1997} SCIENCE
    Vol. {275}({5296}), pp. {83-86} 
    article  
    Abstract: Regional brain activation was assessed by mapping of Fos-related protein expression in rats trained to self-administration of intravenous nicotine and cocaine. Both drugs produced specific overlapping patterns of activation in the shell and the core of the nucleus accumbens, medial prefrontal cortex, and medial caudate areas, but not in the amygdala. Thus, the reinforcing properties of cocaine and nicotine map on selected structures of the terminal fields of the mesocorticolimbic dopamine system, supporting the idea that common substrates for these addictive drugs exist.
    BibTeX:
    @article{Pich1997,
      author = {Pich, EM and Pagliusi, SR and Tessari, M and TalabotAyer, D and vanHuijsduijnen, RH and Chiamulera, C},
      title = {Common neural substrates for the addictive properties of nicotine and cocaine},
      journal = {SCIENCE},
      year = {1997},
      volume = {275},
      number = {5296},
      pages = {83-86}
    }
    
    Pierce, R., Bell, K., Duffy, P. & Kalivas, P. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization {1996} JOURNAL OF NEUROSCIENCE
    Vol. {16}({4}), pp. {1550-1560} 
    article  
    Abstract: Rats were pretreated with daily cocaine or saline injections for 1 week. The rats treated with daily cocaine were separated into two groups: a sensitized group of animals demonstrating >20% increase in motor activity on the last injection compared with the first injection of daily cocaine, and a nonsensitized group showing <20% elevation. At 2-3 weeks after the last daily injection, four experiments were performed to assess changes in excitatory amino acid (EAA) transmission in the nucleus accumbens produced by repeated cocaine administration. (1) Rats were challenged with a microinjection of AMPA into the shell or core of the nucleus accumbens. The sensitized rats demonstrated greater motor activity than did the saline-pretreated or nonsensitized animals after AMPA injection into either subnucleus. (2) It was shown that the behavioral distinction between sensitized, nonsensitized, and control rats in behavioral responsiveness to AMPA was not mediated by differences in AMPA-induced dopamine release. (3) The extracellular content of glutamate was measured after a cocaine challenge given at 21 d of withdrawal. Cocaine elevated the levels of glutamate in the core of sensitized rats, but not of nonsensitized or control rats. (4) Microinjection of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione into the core abolished the augmented motor response to a cocaine challenge in sensitized rats, but was without effect on cocaine-induced motor activity in nonsensitized animals. These results indicate that repeated cocaine administration increases EAA transmission in the nucleus accumbens only in rats that develop behavioral sensitization to cocaine.
    BibTeX:
    @article{Pierce1996,
      author = {Pierce, RC and Bell, K and Duffy, P and Kalivas, PW},
      title = {Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1996},
      volume = {16},
      number = {4},
      pages = {1550-1560}
    }
    
    Pierce, R. & Kalivas, P. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants {1997} BRAIN RESEARCH REVIEWS
    Vol. {25}({2}), pp. {192-216} 
    article  
    Abstract: Repeated exposure to psychostimulants such as cocaine and amphetamine produces behavioral sensitization, which is characterized by an augmented locomotor response to a subsequent psychostimulant challenge injection. Experimentation focused on the neural underpinnings of behavioral sensitization has progressed from a singular focus on dopamine transmission in the nucleus accumbens and striatum to the study of cellular and molecular mechanisms that occur throughout the neural circuitry in which the mesocorticolimbic dopamine projections are embedded. This research effort has yielded a conglomerate of data that has resisted simple interpretations, primarily because no single neuronal effect is likely to be responsible for the expression of behavioral sensitization. The present review examines the literature and critically evaluates the extent to which the neural consequences of repeated psychostimulant administration are associated with the expression of behavioral sensitization. The neural alterations found to contribute to the long-term expression of behavioral sensitization are centered in a collection of interconnected limbic nuclei, which are termed the `motive' circuit. This neural circuit is used as a template to organize the relevant biochemical and molecular findings into a model of the expression of behavioral sensitization. (C) 1997 Elsevier Science B.V.
    BibTeX:
    @article{Pierce1997,
      author = {Pierce, RC and Kalivas, PW},
      title = {A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {1997},
      volume = {25},
      number = {2},
      pages = {192-216}
    }
    
    PIERCE, R. & KALIVAS, P. AMPHETAMINE PRODUCES SENSITIZED INCREASES IN LOCOMOTION AND EXTRACELLULAR DOPAMINE PREFERENTIALLY IN THE NUCLEUS-ACCUMBENS SHELL OF RATS ADMINISTERED REPEATED COCAINE {1995} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {275}({2}), pp. {1019-1029} 
    article  
    Abstract: Alterations in dopamine transmission in the nucleus accumbens, which is composed of two anatomically distinct compartments termed the shell and core, contribute to the expression of cocaine-induced behavioral sensitization. To test potential presynaptic components of behavioral sensitization, the behavioral and neurochemical response to amphetamine administration in the accumbens shell and core was measured at early (days 1-3) and late (days 20-22) withdrawal in rats pretreated with systemic cocaine (15 mg/kg x 2 days, 30 mg/kg x 5 days) or saline. Behavioral sensitization was observed at late, but not early withdrawal when amphetamine was microinjected into the nucleus accumbens shell of cocaine-pretreated rats. There were no significant differences between cocaine- and saline-pretreated animals when behavior was monitored after amphetamine injections into the core at either withdrawal period. After both withdrawal periods, the amphetamine-induced increase in extracellular dopamine was potentiated among cocaine-pretreated animals in the shell by the local administration of amphetamine (0.03, 0.3, 3.0 and 30 mu M through the dialysis probe). In the core at early withdrawal there was tolerance to the amphetamine-induced increase in extracellular dopamine in the cocaine group, whereas there was no difference between the repeated saline and cocaine groups at late withdrawal. In a second experiment designed to evaluate potential postsynaplic influences, the D-1 partial agonist, SKF-38393 (0.01 or 0.1 mu g/side), was microinjected into the nucleus accumbens core or shell regions after behavioral sensitization to cocaine. Although there was a motor-stimulant effect of SKF-38393 at both withdrawal periods, there was no difference between rats pretreated with repeated cocaine or saline. Collectively, these results demonstrate that the augmentation in dopamine transmission in the nucleus accumbens that is associated with behavioral sensitization is more robust in the shell than the core.
    BibTeX:
    @article{PIERCE1995,
      author = {PIERCE, RC and KALIVAS, PW},
      title = {AMPHETAMINE PRODUCES SENSITIZED INCREASES IN LOCOMOTION AND EXTRACELLULAR DOPAMINE PREFERENTIALLY IN THE NUCLEUS-ACCUMBENS SHELL OF RATS ADMINISTERED REPEATED COCAINE},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1995},
      volume = {275},
      number = {2},
      pages = {1019-1029}
    }
    
    PIJNENBU.AJ & VANROSSU.JM STIMULATION OF LOCOMOTOR ACTIVITY FOLLOWING INJECTION OF DOPAMINE INTO NUCLEUS ACCUMBENS {1973} JOURNAL OF PHARMACY AND PHARMACOLOGY
    Vol. {25}({12}), pp. {1003-1005} 
    article  
    BibTeX:
    @article{PIJNENBU.AJ1973,
      author = {PIJNENBU.AJ and VANROSSU.JM},
      title = {STIMULATION OF LOCOMOTOR ACTIVITY FOLLOWING INJECTION OF DOPAMINE INTO NUCLEUS ACCUMBENS},
      journal = {JOURNAL OF PHARMACY AND PHARMACOLOGY},
      year = {1973},
      volume = {25},
      number = {12},
      pages = {1003-1005}
    }
    
    PIJNENBURG, A., HONIG, W. & VANROSSUM, J. INHIBITION OF D-AMPHETAMINE-INDUCED LOCOMOTOR ACTIVITY BY INJECTION OF HALOPERIDOL INTO NUCLEUS ACCUMBENS OF RAT {1975} PSYCHOPHARMACOLOGIA
    Vol. {41}({2}), pp. {87-95} 
    article  
    BibTeX:
    @article{PIJNENBURG1975,
      author = {PIJNENBURG, AJJ and HONIG, WMM and VANROSSUM, JM},
      title = {INHIBITION OF D-AMPHETAMINE-INDUCED LOCOMOTOR ACTIVITY BY INJECTION OF HALOPERIDOL INTO NUCLEUS ACCUMBENS OF RAT},
      journal = {PSYCHOPHARMACOLOGIA},
      year = {1975},
      volume = {41},
      number = {2},
      pages = {87-95}
    }
    
    Pilla, M., Perachon, S., Sautel, F., Garrido, F., Mann, A., Wermuth, C., Schwartz, J., Everitt, B. & Sokoloff, P. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D-3 receptor agonist {1999} NATURE
    Vol. {400}({6742}), pp. {371-375} 
    article  
    Abstract: Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving and relapse in abstinent human substance abusers(1-4). In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction(5-7). Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction(3). Converging pharmacological(8,9), human post-mortem(10) and genetic(11) studies implicate the dopamine D-3 receptor(12) in drug addiction. Here we have designed BP 897, the first D-3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D-3-receptor genes. BP 897 is a partial agonist in vitro and acts in vivo as either an agonist or an antagonist. We show that BP 897 inhibits cocaine-seeking behaviour that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects. Our data indicate that compounds like BP 897 could be used for reducing the drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli.
    BibTeX:
    @article{Pilla1999,
      author = {Pilla, M and Perachon, S and Sautel, F and Garrido, F and Mann, A and Wermuth, CG and Schwartz, JC and Everitt, BJ and Sokoloff, P},
      title = {Selective inhibition of cocaine-seeking behaviour by a partial dopamine D-3 receptor agonist},
      journal = {NATURE},
      year = {1999},
      volume = {400},
      number = {6742},
      pages = {371-375}
    }
    
    Pliakas, A., Carlson, R., Neve, R., Konradi, C., Nestler, E. & Carlezon, W. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens {2001} JOURNAL OF NEUROSCIENCE
    Vol. {21}({18}), pp. {7397-7403} 
    article  
    Abstract: Drugs of abuse regulate the transcription factor cAMP response element-binding protein (CREB) in striatal regions, including the nucleus accumbens (NAc). To explore how regulation of CREB in the NAc affects behavior, we used herpes simplex virus (HSV) vectors to elevate CREB expression in this region or to overexpress a dominant-negative mutant CREB (mCREB) that blocks CREB function. Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine, indicating increased cocaine reward. Conversely, rats treated with HSV-CREB spent less time in cocaine-associated environments, indicating increased cocaine aversion. Studies in which drug-environment pairings were varied to coincide with either the early or late effects of cocaine suggest that CREB-associated place aversions reflect increased cocaine withdrawal. Because cocaine withdrawal can be accompanied by symptoms of depression, we examined how altered CREB function in the NAc affects behavior in the forced swim test (FST). Elevated CREB expression increased immobility in the FST, an effect that is opposite to that caused by standard antidepressants and is consistent with a link between CREB and dysphoria. Conversely, overexpression of mCREB decreased immobility, an effect similar to that caused by antidepressants. Moreover, the kappa opioid receptor antagonist nor-Binaltorphimine decreased immobility in HSV-CREB- and HSV-mCREB-treated rats, suggesting that CREB-mediated induction of dynorphin (an endogenous kappa receptor ligand) contributes to immobility behavior in the FST Exposure to the FST itself dramatically increased CREB function in the NAc. These findings raise the possibility that CREB-mediated transcription within the NAc regulates dysphoric states.
    BibTeX:
    @article{Pliakas2001,
      author = {Pliakas, AM and Carlson, RR and Neve, RL and Konradi, C and Nestler, EJ and Carlezon, WA},
      title = {Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2001},
      volume = {21},
      number = {18},
      pages = {7397-7403}
    }
    
    Pontieri, F., Tanda, G. & DiChiara, G. Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the `'shell'' as compared with the `'core'' of the rat nucleus accumbens {1995} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {92}({26}), pp. {12304-12308} 
    article  
    Abstract: The nucleus accumbens is considered a critical target of the action of drugs of abuse. In this nucleus a `'shell'' and a `'core'' have been distinguished on the basis of anatomical and histochemical criteria, The present study investigated the effect in freely moving rats of intravenous cocaine, amphetamine, and morphine on extracellular dopamine concentrations in the nucleus accumbens shell and core by means of microdialysis with vertically implanted concentric probes. Doses selected were in the range of those known to sustain drug self-administration in rats, Morphine, at 0.2 and 0.4 mg/kg, and cocaine, at 0.5 mg/kg, increased extracellular dopamine selectively in the shell, Higher doses of cocaine (1.0 mg/kg) and the lowest dose of amphetamine tested (0.125 mg/kg) increased extracellular dopamine both in the shell and in the core, but the effect was significantly more pronounced in the shell compared with the core, Only the highest dose of amphetamine (0.250 mg/kg) increased extracellular dopamine in the shell and in the core to a similar extent, The present results provide in vivo neurochemical evidence for a functional compartmentation within the nucleus accumbens and for a preferential effect of psychostimulants and morphine in the shell of the nucleus accumbens at doses known to sustain intravenous drug self-administration.
    BibTeX:
    @article{Pontieri1995,
      author = {Pontieri, FE and Tanda, G and DiChiara, G},
      title = {Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the `'shell'' as compared with the `'core'' of the rat nucleus accumbens},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1995},
      volume = {92},
      number = {26},
      pages = {12304-12308}
    }
    
    Pontieri, F., Tanda, G., Orzi, F. & DiChiara, G. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs {1996} NATURE
    Vol. {382}({6588}), pp. {255-257} 
    article  
    Abstract: THE question of whether nicotine, the neuroactive compound of tobacco, is addictive has been open to considerable scientific and public discussion. Although it can serve as a positive reinforcer in several animal species, including man, nicotine is thought to be a weak reinforcer in comparison with addictive drugs such as cocaine and heroin(1,2), and has been argued to be habit forming but not addictive(3,4). Here we report that intravenous nicotine in the rat, at doses known to maintain self-administration, stimulates local energy metabolism, as measured by 2-deoxyglucose autoradiography, and dopamine transmission, as estimated by brain microdialysis, in the shell of the nucleus accumbens. These neurochemical and metabolic effects are qualitatively similar to those of other drugs, such as cocaine, amphetamine and morphine, which have strong addictive properties(5-7). Our results provide functional and neurochemical evidence that there are specific neurobiological commonalities between nicotine and addictive drugs.
    BibTeX:
    @article{Pontieri1996,
      author = {Pontieri, FE and Tanda, G and Orzi, F and DiChiara, G},
      title = {Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs},
      journal = {NATURE},
      year = {1996},
      volume = {382},
      number = {6588},
      pages = {255-257}
    }
    
    Reiner, A., Perkel, D., Bruce, L., Butler, A., Csillag, A., Kuenzel, W., Medina, L., Paxinos, G., Shimizu, T., Striedter, G., Wild, M., Ball, G., Durand, S., Gunturkun, O., Lee, D., Mello, C., Powers, A., White, S., Hough, G., Kubikova, L., Smulders, T., Wada, K., Dugas-Ford, J., Husband, S., Yamamoto, K., Yu, J., Siang, C. & Jarvis, E. Revised nomenclature for avian telencephalon and some related brainstem nuclei {2004} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {473}({3}), pp. {377-414} 
    article DOI  
    Abstract: The standard nomenclature that has been used for many telencephalic and related brainstem structures in birds is based on flawed assumptions of homology to mammals. In particular, the outdated terminology implies that most of the avian telencephalon is a hypertrophied basal ganglia, when it is now clear that most of the avian telencephalon is neurochemically, hodologically, and functionally comparable to the mammalian neocortex, claustrum, and pallial amygdala (all of which derive from the pallial sector of the developing telencephalon). Recognizing that this promotes misunderstanding of the functional organization of avian brains and their evolutionary relationship to mammalian brains, avian brain specialists began discussions to rectify this problem, culminating in the Avian Brain Nomenclature Forum held at Duke University in July 2002, which approved a new terminology for avian telencephalon and some allied brainstem cell groups. Details of this new terminology are presented here, as is a rationale for each name change and evidence for any homologies implied by the new names. Revisions for the brainstem focused on vocal control, catecholaminergic, cholinergic, and basal ganglia-related nuclei. For example, the Forum recognized that the hypoglossal nucleus had been incorrectly identified as the nucleus intermedius in the Karten and Hodos (1967) pigeon brain atlas, and what was identified as the hypoglossal nucleus in that atlas should instead be called the supraspinal nucleus. The locus ceruleus of this and other avian atlases was noted to consist of a caudal noradrenergic part homologous to the mammalian locus coeruleus and a rostral region corresponding to the mammalian A8 dopaminergic cell group. The midbrain dopaminergic cell group in birds known as the nucleus tegmenti pedunculo-pontinus pars compacta was recognized as homologous to the mammalian substantia nigra pars compacta and was renamed accordingly; a group of gamma-aminobutyric acid (GABA)ergic neurons at the lateral edge of this region was identified as homologous to the mammalian substantia nigra pars reticulata and was also renamed accordingly. A field of cholinergic neurons in the rostral avian hindbrain was named the nucleus pedunculopontinus tegmenti, whereas the anterior nucleus of the ansa lenticularis in the avian diencephalon was renamed the subthalamic nucleus, both for their evident mammalian homologues. For the basal (i.e., subpallial) telencephalon, the actual parts of the basal ganglia were given names reflecting their now evident homologues. For example, the lobus parolfactorius and paleostriatum augmentatum were acknowledged to make up the dorsal subdivision of the striatal part of the basal ganglia and were renamed as the medial and lateral striatum. The paleostriaturn primitivum was recognized as homologous to the mammalian globus pallidus and renamed as such. Additionally, the rostroventral part of what was called the lobus parolfactorius was acknowledged as comparable to the mammalian nucleus accumbens, which, together with the olfactory tubercle, was noted to be part of the ventral striatum in birds. A ventral pallidum, a basal cholinergic cell group, and medial and lateral bed nuclei of the stria terminalis were also recognized. The dorsal (i.e., pallial) telencephalic regions that had been erroneously named to reflect presumed homology to striatal parts of mammalian basal ganglia were renamed as part of the pallium, using prefixes that retain most established abbreviations, to maintain continuity with the outdated nomenclature. We concluded, however, that one-to-one (i.e., discrete) homologies with mammals are still uncertain for most of the telencephalic pallium in birds and thus the new pallial terminology is largely devoid of assumptions of one-to-one homologies with mammals. The sectors of the hyperstriatum composing the Wulst (i.e., the hyperstyiatum accessorium intermedium, and dorsale), the hyperstriatum ventrale, the neostriatum, and the archistriatum have been renamed (respectively) the hyperpallium (hypertrophied pallium), the mesopallium (middle pallium), the nidopallium (nest pallium), and the arcopallium (arched pallium). The posterior part of the archistriatum has been renamed the posterior pallial amygdala, the nucleus taeniae recognized as part of the avian amygdala, and a region inferior to the posterior paleostriaturn primitivum included as a subpallial part of the avian amygdala. The names of some of the laminae and fiber tracts were also changed to reflect current understanding of the location of pallial and subpallial sectors of the avian telencephalon. Notably, the lamina medularis dorsalis has been renamed the pallial-subpallial lamina. We urge all to use this new terminology, because we believe it will promote better communication among neuroscientists. (C) 2004 Wiley-Liss, Inc.
    BibTeX:
    @article{Reiner2004,
      author = {Reiner, A and Perkel, DJ and Bruce, LL and Butler, AB and Csillag, A and Kuenzel, W and Medina, L and Paxinos, G and Shimizu, T and Striedter, G and Wild, M and Ball, GF and Durand, S and Gunturkun, O and Lee, DW and Mello, CV and Powers, A and White, SA and Hough, G and Kubikova, L and Smulders, TV and Wada, K and Dugas-Ford, J and Husband, S and Yamamoto, K and Yu, J and Siang, C and Jarvis, ED},
      title = {Revised nomenclature for avian telencephalon and some related brainstem nuclei},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {2004},
      volume = {473},
      number = {3},
      pages = {377-414},
      doi = {{10.1002/cne.20118}}
    }
    
    Richardson, N. & Roberts, D. Progressive ratio schedules in drug self-administration studies in rats: A method to evaluate reinforcing efficacy {1996} JOURNAL OF NEUROSCIENCE METHODS
    Vol. {66}({1}), pp. {1-11} 
    article  
    Abstract: Drug self-administration studies have recently employed progressive ratio (PR) schedules to examine psychostimulant and opiate reinforcement. This review addresses the technical, statistical, and theoretical issues related to the use of the PR schedule in self-administration studies in rats. Session parameters adopted for use in our laboratory and the considerations relevant to them are described. The strengths and weaknesses of the PR schedule are also discussed.
    BibTeX:
    @article{Richardson1996,
      author = {Richardson, NR and Roberts, DCS},
      title = {Progressive ratio schedules in drug self-administration studies in rats: A method to evaluate reinforcing efficacy},
      journal = {JOURNAL OF NEUROSCIENCE METHODS},
      year = {1996},
      volume = {66},
      number = {1},
      pages = {1-11}
    }
    
    Rilling, J., Gutman, D., Zeh, T., Pagnoni, G., Berns, G. & Kilts, C. A neural basis for social cooperation {2002} NEURON
    Vol. {35}({2}), pp. {395-405} 
    article  
    Abstract: Cooperation based on reciprocal altruism has evolved in only a small number of species, yet it constitutes the core behavioral principle of human social life. The iterated Prisoner's Dilemma Game has been used to model this form of cooperation. We used fMRI to scan 36 women as they played an iterated Prisoner's Dilemma Game with another woman to investigate the neurobiological basis of cooperative social behavior. Mutual cooperation was associated with consistent activation in brain areas that have been linked with reward processing: nucleus accumbens, the caudate nucleus, ventromedial frontal/orbitofrontal cortex, and rostral anterior cingulate cortex. We propose that activation of this neural network positively reinforces reciprocal altruism, thereby motivating subjects to resist the temptation to selfishly accept but not reciprocate favors.
    BibTeX:
    @article{Rilling2002,
      author = {Rilling, JK and Gutman, DA and Zeh, TR and Pagnoni, G and Berns, GS and Kilts, CD},
      title = {A neural basis for social cooperation},
      journal = {NEURON},
      year = {2002},
      volume = {35},
      number = {2},
      pages = {395-405}
    }
    
    Robbe, D., Kopf, M., Remaury, A., Bockaert, J. & Manzoni, O. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens {2002} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {99}({12}), pp. {8384-8388} 
    article DOI  
    Abstract: Do endocannabinoids (eCBs) participate in long-term synaptic plasticity in the brain? Using pharmacological approaches and genetically altered mice, we show that stimulation of prelimbic cortex afferents at naturally occurring frequencies causes a long-term depression of nucleus accumbens glutamatergic synapses mediated by eCB release and presynaptic CB1 receptors. Translation of glutamate synaptic transmission into eCB retrograde signaling involved metabotropic glutamate receptors and postsynaptic intracellular Ca2+ stores. These findings unveil the role of the eCB system in activity-dependent long-term synaptic plasticity and identify a mechanism by which marijuana can alter synaptic functions in the endogenous brain reward system.
    BibTeX:
    @article{Robbe2002,
      author = {Robbe, D and Kopf, M and Remaury, A and Bockaert, J and Manzoni, OJ},
      title = {Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {2002},
      volume = {99},
      number = {12},
      pages = {8384-8388},
      doi = {{10.1073/pnas.122149199}}
    }
    
    Robbins, T. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry {2002} PSYCHOPHARMACOLOGY
    Vol. {163}({3-4}), pp. {362-380} 
    article DOI  
    Abstract: Rationale: The developmental history and application of the 5-choice serial reaction time task (5CSRTT) for measuring effects of drugs and other manipulations on attentional performance (and stimulus control) in rats is reviewed. Objectives: The 5CSRTT has been used for measuring effects of systemic drug treatments and also central manipulations such as neurochemical lesions on various aspects of attentional control, including sustained, selective and divided attention - and is relevant to the definition of neural systems of attention and applications to human disorders such as attention deficit/hyperactivity disorder (ADHD) and Alzheimer's disease. Methods: The 5CSRTT is implemented in a specially designed operant chamber with multiple response locations ('nine-hole box') using food reinforcers to maintain performance on baseline sessions (about 100 trials) at criterion levels of accuracy and trials completed. The 5CSRTT can be used for measuring various aspects of attentional control over performance with its main measures of accuracy, premature responding, correct response latencies and latency to collect earned food pellets. Results: The data reviewed include studies mainly of systemic and intra-cerebral effects of adrenoceptor, dopamine receptor, serotoninergic receptor and cholinergic receptor agents. These are compared with investigations of effects of selective chemical neurotoxins and excitotoxins applied to discrete parts of the forebrain, in order to define the neural and neurochemical substrates of attentional function. Furthermore, these results are integrated with findings from in vivo microdialysis in freely moving rats or metabolic studies. Conclusions: The monoaminergic and cholinergic systems appear to play separable roles in different aspects of performance controlled by the 5CSRTT, in neural systems centred on the prefrontal cortex, cingulate cortex and striatum. These conclusions are considered in the methodological and theoretical context of other psychopharmacological studies of attention in animals and humans.
    BibTeX:
    @article{Robbins2002,
      author = {Robbins, TW},
      title = {The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry},
      journal = {PSYCHOPHARMACOLOGY},
      year = {2002},
      volume = {163},
      number = {3-4},
      pages = {362-380},
      doi = {{10.1107/s00213-002-1154-7}}
    }
    
    Robbins, T. Arousal systems and attentional processes {1997} BIOLOGICAL PSYCHOLOGY
    Vol. {45}({1-3}), pp. {57-71} 
    article  
    Abstract: Unitary concepts of arousal have outlived their usefulness and their psychological fractionation corresponds to a similar chemical differentiation of the reticular formation of the brain. Neurobiological characteristics of the monoaminergic and cholinergic systems can be described in terms of their anatomical, electrophysiological and neurochemical properties. Functional studies suggest that the coeruleo-cortical noradrenergic system, under certain circumstances, is implicated in processes of selective attention, that the mesolimbic and mesostriatal dopaminergic systems contribute to different forms of behavioural activation, and that the cortical cholinergic projections have fundamental roles in the cortical processing of signals, affecting attentional and mnemonic processes. The ascending serotoninergic systems contribute to behavioural inhibition and appear to oppose the functions of the other systems in several ways. (C) 1997 Elsevier Science B.V.
    BibTeX:
    @article{Robbins1997,
      author = {Robbins, TW},
      title = {Arousal systems and attentional processes},
      journal = {BIOLOGICAL PSYCHOLOGY},
      year = {1997},
      volume = {45},
      number = {1-3},
      pages = {57-71},
      note = {Workshop on Psychophysiology of Mental Resources - Mental Resources: Intensive and Selective Aspects, AMSTERDAM, NETHERLANDS, SEP 05-08, 1995}
    }
    
    Robbins, T. & Everitt, B. Neurobehavioural mechanisms of reward and motivation {1996} CURRENT OPINION IN NEUROBIOLOGY
    Vol. {6}({2}), pp. {228-236} 
    article  
    Abstract: The analysis of the behavioural and neural mechanisms of reinforcement and motivation has benefited from the recent application of learning theory and better anatomical knowledge of the connectivity of certain key neural structures, such as the nucleus accumbens. This progress has enabled the dissection of motivational processes into components that can begin to be related to the functioning of specific limbic cortical structures that project to different compartments of the ventral striatum.
    BibTeX:
    @article{Robbins1996,
      author = {Robbins, TW and Everitt, BJ},
      title = {Neurobehavioural mechanisms of reward and motivation},
      journal = {CURRENT OPINION IN NEUROBIOLOGY},
      year = {1996},
      volume = {6},
      number = {2},
      pages = {228-236}
    }
    
    ROBERTS, D., KOOB, G., KLONOFF, P. & FIBIGER, H. EXTINCTION AND RECOVERY OF COCAINE SELF-ADMINISTRATION FOLLOWING 6-HYDROXYDOPAMINE LESIONS OF THE NUCLEUS ACCUMBENS {1980} PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
    Vol. {12}({5}), pp. {781-787} 
    article  
    BibTeX:
    @article{ROBERTS1980,
      author = {ROBERTS, DCS and KOOB, GF and KLONOFF, P and FIBIGER, HC},
      title = {EXTINCTION AND RECOVERY OF COCAINE SELF-ADMINISTRATION FOLLOWING 6-HYDROXYDOPAMINE LESIONS OF THE NUCLEUS ACCUMBENS},
      journal = {PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR},
      year = {1980},
      volume = {12},
      number = {5},
      pages = {781-787}
    }
    
    ROBERTSON, G. & FIBIGER, H. NEUROLEPTICS INCREASE C-FOS EXPRESSION IN THE FOREBRAIN - CONTRASTING EFFECTS OF HALOPERIDOL AND CLOZAPINE {1992} NEUROSCIENCE
    Vol. {46}({2}), pp. {315-328} 
    article  
    Abstract: The mechanisms by which the atypical neuroleptic clozapine produces its therapeutic effects in the treatment of schizophrenia without causing the extrapyramidal side effects that are characteristic of most antipsychotic drugs remain unclear. Recently, a single injection of the typical antipsychotic haloperidol has been shown to increase c-fos expression in the striatum [Dragunow et al. (1990) Neuroscience 37, 287-294]. C-fos is a proto-oncogene that encodes a 55,000 mol. wt phosphoprotein, Fos, which is thought to assist in the regulation of ``target genes'' containing an AP-1 binding site. Because a wide variety of physiological and pharmacological stimuli increase c-fos expression, it has been proposed that Fos immunohistochemistry might be useful in mapping functional pathways in the central nervous system. The present experiments examined some potential neuroanatomical differences in the actions of clozapine and haloperidol by comparing their effects on c-fos expression in the medial prefrontal cortex, nucleus accumbens, striatum and lateral septum. The effects of the selective dopamine receptor antagonists SCH 23390 (D1) and raclopride (D2) were also examined. Haloperidol (0.5, 1 mg/kg) and raclopride (1, 2 mg/kg) produced large increases in the number of Fos-containing neurons in the striatum and nucleus accumbens. SCH 23390 (0.5, 1 mg/kg) reduced the number of Fos-positive neurons in the nucleus accumbens and striatum, and had no effect in the other regions. Neither haloperidol nor raclopride increased the number of Fos-positive neurons in the medial prefronal cortex. Haloperidol, but not raclopride, produced a modest increase in c-fos expression in the lateral septal nucleus. Clozapine (10, 20 mg/kg) was without effect in the striatum; however, it significantly increased the number of Fos-positive neurons in the nucleus accumbens, medial prefrontal cortex and lateral septal nucleus. Destruction of mesotelencephalic dopaminergic neurons with 6-hydroxydopamine abolished the increase in Fos expression in the nucleus accumbens and striatum produced by haloperidol and raclopride, and also blocked the clozapine-induced increase in the nucleus accumbens. However, the inductive effects of clozapine and haloperidol on c-fos expression in the lateral septal nucleus and of clozapine in the medial prefrontal cortex were not affected by the 6-hydroxydopamine lesions. These results suggest that clozapine's unique therapeutic profile may be related to its failure to induce Fos in the striatum as well as its idiosyncratic actions in the lateral septum and medial prefrontal cortex. The effects of clozapine in these latter regions do not appear to be mediated by dopaminergic mechanisms.
    BibTeX:
    @article{ROBERTSON1992,
      author = {ROBERTSON, GS and FIBIGER, HC},
      title = {NEUROLEPTICS INCREASE C-FOS EXPRESSION IN THE FOREBRAIN - CONTRASTING EFFECTS OF HALOPERIDOL AND CLOZAPINE},
      journal = {NEUROSCIENCE},
      year = {1992},
      volume = {46},
      number = {2},
      pages = {315-328}
    }
    
    ROBERTSON, G., MATSUMURA, H. & FIBIGER, H. INDUCTION-PATTERNS OF FOS-LIKE IMMUNOREACTIVITY IN THE FOREBRAIN AS PREDICTORS OF ATYPICAL ANTIPSYCHOTIC ACTIVITY {1994} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {271}({2}), pp. {1058-1066} 
    article  
    Abstract: Clozapine and haloperidol produce different induction patterns of c-fos expression in the forebrain, with haloperidol increasing Fos-like immunoreactivity (FLI) in the striatum, nucleus accumbens, lateral septal nucleus and clozapine producing such effects in the nucleus accumbens, prefrontal cortex and lateral septal nucleus. Accordingly, it was deemed possible that this approach may be useful in characterizing compounds with known or suggested antipsychotic actions. We therefore examined the effects of 17 compounds considered to be either typical, or atypical, antipsychotics on FLI in the prefrontal cortex, medial and dorsolateral striatum, nucleus accumbens and the lateral septal nucleus. Consistent with the hypothesis that the prefrontal cortex may be a target for some antipsychotic actions, FLI was elevated in this structure by clozapine, ICI 204,636, fluperlapine, RMI-81,582, remoxipride, molindone, melperone and tiospirone. Likewise, the ability of all of the compounds, except for risperidone, to enhance FLI in the lateral septal nucleus suggests that this limbic region also may be an important locus of antipsychotic action. All of the compounds examined elevated FLI in the nucleus accumbens and medial striatum, indicating that potential antipsychotic activity is predicted most consistently on this basis. Neuroleptics with a clearly documented liability for producing extrapyramidal side effects (EPS) such as chlorpromazine, fluphenazine, haloperidol, loxapine, metoclopramide and molindone elevated FLI in the dorsolateral striatum. in contrast, compounds unlikely to produce EPS such as clozapine, thioridazine, risperidone, remoxipride, fluperlapine, sulpiride, melperone and RMI-81,582 either failed to increase or produced minor elevations in FLI in the dorsolateral striatum. Hence, the ability of a neuroleptic to increase FLI in the dorsolateral striatum predicted reasonably well its propensity to induce EPS. However, in order to devise a more precise classification scheme, we compared the difference between the number of neurons which displayed neuroleptic-induced FLI in the nucleus accumbens vs, that in the dorsolateral striatum after administration of each of the 17 compounds. This difference, referred to as the atypical index, was always positive for atypical antipsychotics and invariably negative for typical neuroleptics. Thus, in every instance it was possible to accurately predict the potential for EPS on the basis of whether the atypical index was positive or negative. These results suggest that Fos immunohistochemistry is a rapid and reliable method for determining the EPS liability of potential antipsychotic agents.
    BibTeX:
    @article{ROBERTSON1994,
      author = {ROBERTSON, GS and MATSUMURA, H and FIBIGER, HC},
      title = {INDUCTION-PATTERNS OF FOS-LIKE IMMUNOREACTIVITY IN THE FOREBRAIN AS PREDICTORS OF ATYPICAL ANTIPSYCHOTIC ACTIVITY},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1994},
      volume = {271},
      number = {2},
      pages = {1058-1066}
    }
    
    Robinson, T. & Berridge, K. Addiction {2003} ANNUAL REVIEW OF PSYCHOLOGY
    Vol. {54}, pp. {25-53} 
    article DOI  
    Abstract: The development of addiction involves a transition from casual to compulsive patterns of drug use. This transition to addiction is accompanied by many drug-induced changes in the brain and associated changes in psychological functions. In this article we present a critical analysis of the major theoretical explanations of how drug-induced alterations in psychological function might cause a transition to addiction. These include: (a) the traditional hedonic view that drug pleasure and subsequent unpleasant withdrawal symptoms are the chief causes of addiction; (b) the view that addiction is due to aberrant learning, especially the development of strong stimulus-response habits; (c) our incentive-sensitization view, which suggests that sensitization of a neural system that attributes incentive salience causes compulsive motivation or ``wanting'' to take addictive drugs; and (d) the idea that dysfunction of frontal cortical systems, which normally regulate decision making and inhibitory control over behavior, leads to impaired judgment and impulsivity in addicts.
    BibTeX:
    @article{Robinson2003,
      author = {Robinson, TE and Berridge, KC},
      title = {Addiction},
      journal = {ANNUAL REVIEW OF PSYCHOLOGY},
      year = {2003},
      volume = {54},
      pages = {25-53},
      doi = {{10.1146/annurev.psych.54.101601.145237}}
    }
    
    Robinson, T. & Berridge, K. Incentive-sensitization and addiction {2001} ADDICTION
    Vol. {96}({1, Sp. Iss. SI}), pp. {103-114} 
    article  
    Abstract: The question of addiction concerns the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that rake place at the expense of most other activities, and the inability ro cease drug-taking, that is, the problem of relapse. In this paper we summarize one view of this process, the ``incentive-sensitization'' view, which we first proposed in 1993. Four major tenets of the incentive-sensitization view are discussed. These are: (1) potentially addictive drugs share the ability to alter brain organization; (2) the brain systems that are altered include there normally involved in the process of incentive motivation and reward; (3) the critical neuroadaptations for addiction render these brain reward systems hypersensitive (''sensitized'') to drugs and drug-associated stimuli; and (4) the brain systems that are sensitized do nor mediate the pleasurable or euphoric effects of drugs (drug ``liking''), but instead they mediate a subcomponent of reward we have termed incentive salience (drug ``wanting'').
    BibTeX:
    @article{Robinson2001,
      author = {Robinson, TE and Berridge, KC},
      title = {Incentive-sensitization and addiction},
      journal = {ADDICTION},
      year = {2001},
      volume = {96},
      number = {1, Sp. Iss. SI},
      pages = {103-114}
    }
    
    Robinson, T. & Berridge, K. The psychology and neurobiology of addiction: an incentive-sensitization view {2000} ADDICTION
    Vol. {95}({8, Suppl. 2}), pp. {S91-S117} 
    article  
    Abstract: The question of addiction specifically concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the ``incentive-sensitization theory of addiction'', which we first proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor sufficient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems. (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward. (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive (''sensitized'') to drugs and drug-associated stimuli. (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug ``liking''), but instead they mediate a subcomponent of reward we have termed incentive salience (drug ``wanting''). We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction.
    BibTeX:
    @article{Robinson2000,
      author = {Robinson, TE and Berridge, KC},
      title = {The psychology and neurobiology of addiction: an incentive-sensitization view},
      journal = {ADDICTION},
      year = {2000},
      volume = {95},
      number = {8, Suppl. 2},
      pages = {S91-S117}
    }
    
    ROBINSON, T. & BERRIDGE, K. THE NEURAL BASIS OF DRUG CRAVING - AN INCENTIVE-SENSITIZATION THEORY OF ADDICTION {1993} BRAIN RESEARCH REVIEWS
    Vol. {18}({3}), pp. {247-291} 
    article  
    Abstract: This paper presents a biopsychological theory of drug addiction, the `Incentive-Sensitization Theory'. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether `wanting' drugs (drug craving) is attributable to `liking' drugs (to the subjective pleasurable effects of drugs)? The theory posits the following. (1) Addictive drugs share the ability to enhance mesotelencephalic dopamine neurotransmission. (2) One psychological function of this neural system is to attribute `incentive salience' to the perception and mental representation of events associated with activation of the system. Incentive salience is a psychological process that transforms the perception of stimuli, imbuing them with salience, making them attractive, `wanted', incentive stimuli. (3) In some individuals the repeated use of addictive drugs produces incremental neuroadaptations in this neural system, rendering it increasingly and perhaps permanently, hypersensitive ('sensitized') to drugs and drug-associated stimuli. The sensitization of dopamine systems is gated by associative learning, which causes excessive incentive salience to be attributed to the act of drug taking and to stimuli associated with drug taking. It is specifically the sensitization of incentive salience, therefore, that transforms ordinary `wanting' into excessive drug craving. (4) It is further proposed that sensitization of the neural systems responsible for incentive salience (for `wanting') can occur independently of changes in neural systems that mediate the subjective pleasurable effects of drugs (drug `liking') and of neural systems that mediate withdrawal. Thus, sensitization of incentive salience can produce addictive behavior (compulsive drug seeking and drug taking) even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family. We review evidence for this view of addiction and discuss its implications for understanding the psychology and neurobiology of addiction.
    BibTeX:
    @article{ROBINSON1993,
      author = {ROBINSON, TE and BERRIDGE, KC},
      title = {THE NEURAL BASIS OF DRUG CRAVING - AN INCENTIVE-SENSITIZATION THEORY OF ADDICTION},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {1993},
      volume = {18},
      number = {3},
      pages = {247-291}
    }
    
    ROBINSON, T., JURSON, P., BENNETT, J. & BENTGEN, K. PERSISTENT SENSITIZATION OF DOPAMINE NEUROTRANSMISSION IN VENTRAL STRIATUM (NUCLEUS ACCUMBENS) PRODUCED BY PRIOR EXPERIENCE WITH (+)-AMPHETAMINE - A MICRODIALYSIS STUDY IN FREELY MOVING RATS {1988} BRAIN RESEARCH
    Vol. {462}({2}), pp. {211-222} 
    article  
    BibTeX:
    @article{ROBINSON1988,
      author = {ROBINSON, TE and JURSON, PA and BENNETT, JA and BENTGEN, KM},
      title = {PERSISTENT SENSITIZATION OF DOPAMINE NEUROTRANSMISSION IN VENTRAL STRIATUM (NUCLEUS ACCUMBENS) PRODUCED BY PRIOR EXPERIENCE WITH (+)-AMPHETAMINE - A MICRODIALYSIS STUDY IN FREELY MOVING RATS},
      journal = {BRAIN RESEARCH},
      year = {1988},
      volume = {462},
      number = {2},
      pages = {211-222}
    }
    
    Robinson, T. & Kolb, B. Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine {1999} EUROPEAN JOURNAL OF NEUROSCIENCE
    Vol. {11}({5}), pp. {1598-1604} 
    article  
    Abstract: Repeated treatment with psychostimulant drugs produces changes in brain and behaviour that far outlast their initial neuropharmacological actions. The nature of persistent drug-induced neurobehavioural adaptations is of interest because they are thought to contribute to the development of dependence and addiction, and other forms of psychopathology, e.g. amphetamine psychosis. There are many reports that psychostimulants produce biochemical adaptations in brain monoamine systems, especially dopamine systems. The purpose of the present study was to determine if they might also alter the morphology of neurons in brain regions that receive monoaminergic innervation. Rats were given repeated injections of either amphetamine or cocaine, or, to control for general motor activity allowed access to running wheel. They were then left undisturbed for 24-25 days before their brains were processed for Golgi-Cox staining. Treatment with either amphetamine or cocaine (but not wheel running experience) increased the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens, and on apical dendrites of layer V pyramidal cells in the prefrontal cortex, cocaine also increased dendritic branching and spine density on the basilar dendrites of pyramidal cells. In addition, both drugs doubled the incidence of branched spines on medium spiny neurons. It is suggested that some of the persistent neurobehavioural consequences of repeated exposure to psychostimulant drugs may be due to their ability to reorganize patterns of synaptic connectivity in the nucleus accumbens and prefrontal cortex.
    BibTeX:
    @article{Robinson1999,
      author = {Robinson, TE and Kolb, B},
      title = {Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine},
      journal = {EUROPEAN JOURNAL OF NEUROSCIENCE},
      year = {1999},
      volume = {11},
      number = {5},
      pages = {1598-1604}
    }
    
    Robinson, T. & Kolb, B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine {1997} JOURNAL OF NEUROSCIENCE
    Vol. {17}({21}), pp. {8491-8497} 
    article  
    Abstract: Experience-dependent changes in behavior are thought to involve structural modifications in the nervous system, especially alterations in patterns of synaptic connectivity. Repeated experience with drugs of abuse can result in very long-lasting changes in behavior, including a persistent hypersensitivity (sensitization) to their psychomotor activating and rewarding effects. It was hypothesized, therefore, that repeated treatment with the psychomotor stimulant drug amphetamine, which produces robust sensitization, would produce structural adaptations in brain regions that mediate its psychomotor activating and rewarding effects. Consistent with this hypothesis, it was found that amphetamine treatment altered the morphology of neurons in the nucleus accumbens and prefrontal cortex. Exposure to amphetamine produced a long-lasting (>1 month) increase in the length of dendrites, in the density of dendritic spines, and in the number of branched spines on the major output cells of the nucleus accumbens, the medium spiny neurons, as indicated by analysis of Golgi-stained material. Amphetamine treatment produced similar effects on the apical (but not basilar) dendrites of layer III pyramidal neurons in the prefrontal cortex. The ability of amphetamine to alter patterns of synaptic connectivity in these structures may contribute to some of the long-term behavioral consequences of repeated amphetamine use, including amphetamine psychosis and addiction.
    BibTeX:
    @article{Robinson1997,
      author = {Robinson, TE and Kolb, B},
      title = {Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1997},
      volume = {17},
      number = {21},
      pages = {8491-8497}
    }
    
    Rocha, B., Fumagalli, F., Gainetdinov, R., Jones, S., Ator, R., Giros, B., Miller, G. & Caron, M. Cocaine self-administration in dopamine-transporter knockout mice {1998} NATURE NEUROSCIENCE
    Vol. {1}({2}), pp. {132-137} 
    article  
    Abstract: The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self-administer cocaine. Mapping of the sites of cocaine binding and neuronal activation suggests an involvement of serotonergic brain regions in this response. These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice.
    BibTeX:
    @article{Rocha1998,
      author = {Rocha, BA and Fumagalli, F and Gainetdinov, RR and Jones, SR and Ator, R and Giros, B and Miller, GW and Caron, MG},
      title = {Cocaine self-administration in dopamine-transporter knockout mice},
      journal = {NATURE NEUROSCIENCE},
      year = {1998},
      volume = {1},
      number = {2},
      pages = {132-137}
    }
    
    RODRIGO, J., SPRINGALL, D., UTTENTHAL, O., BENTURA, M., ABADIAMOLINA, F., RIVEROSMORENO, V., MARTINEZMURILLO, R., POLAK, J. & MONCADA, S. LOCALIZATION OF NITRIC-OXIDE SYNTHASE IN THE ADULT-RAT BRAIN {1994} PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES
    Vol. {345}({1312}), pp. {175-221} 
    article  
    Abstract: The distribution of the immunoreactivity to nitric oxide synthase has been examined from rostral to caudal areas of the rat central nervous system using light microscopy. Endogenous nitric oxide synthase was located using a specific polyclonal antiserum, produced against affinity purified nitric oxide synthase from whole rat brain, following the avidin-biotin peroxidase procedure. Immunoreactive cell bodies and processes showed a widespread distribution in the brain. In the telencephalon, immunoreactive structures were distributed in all areas of the cerebral cortex, the ventral endopiriform nucleus and claustrum, the main and accessory olfactory bulb, the anterior and posterior olfactory nuclei, the precommisural hippocampus, the taenia tecta, the nucleus accumbens, the stria terminalis, the caudate putamen, the olfactory tubercle and islands of Calleja, septum, globus pallidus and substantia innominata, hippocampus and amygdala. In the diencephalon, the immunoreactivity was largely found in both the hypothalamus and thalamus. In the hypothalamus, immunoreactive cell bodies were characteristically located in the perivascular-neurosecretory systems and mamillary bodies. In addition, immunoreactive nerve fibres were detected in the median eminence of the infundibular stem. The mesencephalon showed nitric oxide synthase immunoreactivity in the ventral tegmental area, the interpeduncular nucleus, the rostral linear nucleus of the raphe and the dorsal raphe nucleus. Immunoreactive structures were also found in the nuclei of the central grey, the peripeduncular nucleus and substantia nigra pars lateralis, the geniculate nucleus and in the superior and inferior colliculi. The pens displayed immunoreactive structures principally in the pedunculopontine and laterodorsal tegmental nuclei, the ventral tegmental nucleus, the reticulotegmental pontine nucleus, the parabrachial nucleus and locus coeruleus. In the medulla oblongata, immunoreactive neurons and processes were detected in the principal sensory trigeminal nucleus, the trapezoid body, the raphe magnus, the pontine reticular nuclei, the supragenual nucleus, the prepositus hypoglossal nucleus, the medial and spinal vestibular nuclei, the dorsal cochlear nucleus, the medullary reticular field, the nucleus of the solitary tract, the gracile and cuneate nuclei, the dorsal nucleus of the vagus nerve and the oral, interpolar and caudal parts of the spinal trigeminal nucleus. In the cerebellum, the stellate and basket cells showed immunoreactivity, which was also seen in the basket terminal fibres of the Purkinje cell layer. Isolated immunoreactive Purkinje cells were found in the vermis and parafloccular regions of the cerebellum. In the granular layer of the cerebellum, the granular cells and glomeruli were also immunoreactive. Numerous positive varicose nerve fibres and occasional neurons were also found in the lateral and interposed cerebellar nuclei. Immunoreactive processes were found close to and penetrating the ependymal cells of the ventricular walls, particularly the lateral ventricles. Immunoreactive cell bodies were also detected in the circumventricular organs, including the subfornical organ and area postrema. Cerebral blood vessels were largely surrounded by varicose immunoreactive neuronal processes forming dense networks. Our demonstration of the widespread distribution of the enzyme nitric oxide synthase in diverse nuclei of the rat brain generally confirms earlier histochemical studies and suggests that this enzyme may affect the function of various neurotransmitter-specific systems. The possible implication of nitric oxide synthase in the regulation of the cerebrospinal fluid system and of cerebral blood circulation is discussed.
    BibTeX:
    @article{RODRIGO1994,
      author = {RODRIGO, J and SPRINGALL, DR and UTTENTHAL, O and BENTURA, ML and ABADIAMOLINA, F and RIVEROSMORENO, V and MARTINEZMURILLO, R and POLAK, JM and MONCADA, S},
      title = {LOCALIZATION OF NITRIC-OXIDE SYNTHASE IN THE ADULT-RAT BRAIN},
      journal = {PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES},
      year = {1994},
      volume = {345},
      number = {1312},
      pages = {175-221}
    }
    
    Roitman, M., Stuber, G., Phillips, P., Wightman, R. & Carelli, R. Dopamine operates as a subsecond modulator of food seeking {2004} JOURNAL OF NEUROSCIENCE
    Vol. {24}({6}), pp. {1265-1271} 
    article DOI  
    Abstract: The dopamine projection to the nucleus accumbens has been implicated in behaviors directed toward the acquisition and consumption of natural rewards. The neurochemical studies that established this link made time-averaged measurements over minutes, and so the precise temporal relationship between dopamine changes and these behaviors is not known. To resolve this, we sampled dopamine every 100 msec using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in the nucleus accumbens of rats trained to press a lever for sucrose. Cues that signal the opportunity to respond for sucrose evoked dopamine release (67 +/- 20 nM) with short latency (0.2 +/- 0.1 sec onset). When the same cues were presented to rats naive to the cue - sucrose pairing, similar dopamine signals were not observed. Thus, cue-evoked increases in dopamine in trained rats reflected a learned association between the cues and sucrose availability. Lever presses for sucrose occurred at the peak of the dopamine surges. After lever presses, and while sucrose was delivered and consumed, no further increases in dopamine were detected. Rather, dopamine returned to baseline levels. Together, the results strongly implicate subsecond dopamine signaling in the nucleus accumbens as a real-time modulator of food-seeking behavior.
    BibTeX:
    @article{Roitman2004,
      author = {Roitman, MF and Stuber, GD and Phillips, PEM and Wightman, RM and Carelli, RM},
      title = {Dopamine operates as a subsecond modulator of food seeking},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2004},
      volume = {24},
      number = {6},
      pages = {1265-1271},
      doi = {{10.1523/JNEUROSCI.3823-03.2004}}
    }
    
    Roozendaal, B. 1999 Curt P. Richter Award - Glucocorticoids and the regulation of memory consolidation {2000} PSYCHONEUROENDOCRINOLOGY
    Vol. {25}({3}), pp. {213-238} 
    article  
    Abstract: This paper summarizes recent findings on the amygdala's role in mediating acute effects of glucocorticoids on memory consolidation in rats. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors (GRs or type II) enhances memory consolidation in a dose-dependent inverted-U fashion. Selective lesions of the basolateral nucleus of the amygdala (BLA) or infusions of beta-adrenoceptor antagonists into the BLA block the memory-modulatory effects of systemic injections of glucocorticoids. Additionally, posttraining infusions of a specific GR agonist administered directly into the BLA enhance memory consolidation, whereas those of a GR antagonist impair. These findings indicate that glucocorticoid effects on memory consolidation are mediated, in part, by an activation of GRs in the BLA and that the effects require beta-adrenergic activity in the BLA. Other findings indicate that the BLA interacts with the hippocampus in mediating glucocorticoid-induced modulatory influences on memory consolidation. Lesions of the BLA or inactivation of beta-adrenoceptors within the BLA also block the memory-modulatory effects of intra-hippocampal administration of a GR agonist or antagonist. These findings are in agreement with the general hypothesis that the BLA integrates hormonal and neuromodulatory influences on memory consolidation. However, the BLA is not a permanent locus of storage for this information, but modulates consolidation processes for explicit/associative memories in other brain regions, including the hippocampus. (C) 2000 Elsevier Science Ltd. All rights reserved.
    BibTeX:
    @article{Roozendaal2000,
      author = {Roozendaal, B},
      title = {1999 Curt P. Richter Award - Glucocorticoids and the regulation of memory consolidation},
      journal = {PSYCHONEUROENDOCRINOLOGY},
      year = {2000},
      volume = {25},
      number = {3},
      pages = {213-238}
    }
    
    ROSSETTI, Z., HMAIDAN, Y. & GESSA, G. MARKED INHIBITION OF MESOLIMBIC DOPAMINE RELEASE - A COMMON FEATURE OF ETHANOL, MORPHINE, COCAINE AND AMPHETAMINE ABSTINENCE IN RATS {1992} EUROPEAN JOURNAL OF PHARMACOLOGY
    Vol. {221}({2-3}), pp. {227-234} 
    article  
    Abstract: Withdrawal of rats from chronic ethanol, morphine, cocaine and amphetamine resulted in a marked reduction in extracellular dopamine (DA) concentration in the ventral striatum as measured by microdialysis. Following ethanol and naloxone-precipitated morphine withdrawal, the time course of DA reduction paralleled that of the withdrawal symptomatology. On the other hand, following discontinuation of chronic cocaine, DA reduction was delayed by over 24 h but persisted for several days. After amphetamine withdrawal the fall in DA occurred more rapidly but the reduction also persisted for several days. The administration of the NMDA receptor antagonist, MK-801, to rats withdrawn from chronic ethanol, morphine or amphetamine, but not from chronic cocaine, readily reversed the fall in DA output. The reduction in extracellular DA during ethanol withdrawal was also reversed by SL 82.0715, another NMDA receptor antagonist.
    BibTeX:
    @article{ROSSETTI1992,
      author = {ROSSETTI, ZL and HMAIDAN, Y and GESSA, GL},
      title = {MARKED INHIBITION OF MESOLIMBIC DOPAMINE RELEASE - A COMMON FEATURE OF ETHANOL, MORPHINE, COCAINE AND AMPHETAMINE ABSTINENCE IN RATS},
      journal = {EUROPEAN JOURNAL OF PHARMACOLOGY},
      year = {1992},
      volume = {221},
      number = {2-3},
      pages = {227-234}
    }
    
    Rubinstein, M., Phillips, T., Bunzow, J., Falzone, T., Dziewczapolski, G., Zhang, G., Fang, Y., Larson, J., McDougall, J., Chester, J., Saez, C., Pugsley, T., Gershanik, O., Low, M. & Grandy, D. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine {1997} CELL
    Vol. {90}({6}), pp. {991-1001} 
    article  
    Abstract: The human dopamine D4 receptor (D4R) has received considerable attention because of its high affinity for the atypical antipsychotic clozapine and the unusually polymorphic nature of its gene. To clarify the in vivo role of the D4R, we produced and analyzed mutant mice (D4R(-/-)) lacking this protein. Although less active in open field tests, D4R(-/-) mice outperformed wildtype mice on the rotarod and displayed locomotor supersensitivity to ethanol, cocaine, and methamphetamine. Biochemical analyses revealed that dopamine synthesis and its conversion to DOPAC were elevated in the dorsal striatum from D4R(-/-) mice. Based on these findings, we propose that the D4R modulates normal, coordinated and drug-stimulated motor behaviors as well as the activity of nigrostriatal dopamine neurons.
    BibTeX:
    @article{Rubinstein1997,
      author = {Rubinstein, M and Phillips, TJ and Bunzow, JR and Falzone, TL and Dziewczapolski, G and Zhang, G and Fang, Y and Larson, JL and McDougall, JA and Chester, JA and Saez, C and Pugsley, TA and Gershanik, O and Low, MJ and Grandy, DK},
      title = {Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine},
      journal = {CELL},
      year = {1997},
      volume = {90},
      number = {6},
      pages = {991-1001}
    }
    
    Sagvolden, T. Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD) {2000} NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
    Vol. {24}({1}), pp. {31-39} 
    article  
    Abstract: A good model of a disorder is one that: (a) mimics, although in a simpler form than the full-blown clinical case, the fundamentals of the behavioral characteristics, in this case of people with Attention-Deficit/Hyperactivity Disorder (AD/HD;face validity); (b) conforms with a theoretical rationale for the disorder (construct validity); and (c) is able to predict aspects of behavior, genetics and neurobiology previously uncharted in the clinics (predictive validity). This article discusses the Spontaneously Hypertensive Rat (SHR) and some other putative animal models of AD/HD. It is argued that although other strains and species may be hyperactive and/or show attention deficits following genetic, environmental or pharmacological interventions, the SHR is presently the only strain shown to have the major behavioral symptoms of AD/HD. This dues not mean that investigating other models cannot give valuable information. (C) 2000 Elsevier Science Ltd. All rights reserved.
    BibTeX:
    @article{Sagvolden2000,
      author = {Sagvolden, T},
      title = {Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD)},
      journal = {NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS},
      year = {2000},
      volume = {24},
      number = {1},
      pages = {31-39},
      note = {Symposium on What can Genetic Models tell us about Attention-Deficit Hyperactivity Disorder, HAMILTON, CANADA, DEC 07-16, 1998}
    }
    
    SALAMONE, J. THE INVOLVEMENT OF NUCLEUS-ACCUMBENS DOPAMINE IN APPETITIVE AND AVERSIVE MOTIVATION {1994} BEHAVIOURAL BRAIN RESEARCH
    Vol. {61}({2}), pp. {117-133} 
    article  
    Abstract: In recent years, considerable emphasis has been placed upon the putative role of nucleus accumbens dopamine systems in appetitive motivation and positive reinforcement. However, considerable evidence indicates that brain dopamine in general, and nucleus accumbens dopamine in particular, is involved in aspects of aversive motivation. Administration of dopamine antagonists or localized interference with nucleus accumbens dopamine systems has been shown to disrupt active avoidance behavior. In addition, accumbens dopamine release and metabolism is activated by a wide variety of stressful conditions. A review of the literature indicates that there are substantial similarities between the characteristics of dopaminergic involvement in appetitive and aversive motivation. There is conflicting evidence about the role of dopamine in emotion, and little evidence to suggest that the profound and consistent changes in instrumental behavior produced by interference with DA systems are due to direct dopaminergic mediation of positive affective responses such as hedonia. It is suggested that nucleus accumbens dopamine is involved in aspects of sensorimotor functions that are involved in both appetitive and aversive motivation.
    BibTeX:
    @article{SALAMONE1994,
      author = {SALAMONE, JD},
      title = {THE INVOLVEMENT OF NUCLEUS-ACCUMBENS DOPAMINE IN APPETITIVE AND AVERSIVE MOTIVATION},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {1994},
      volume = {61},
      number = {2},
      pages = {117-133}
    }
    
    Salamone, J. & Correa, M. Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine {2002} BEHAVIOURAL BRAIN RESEARCH
    Vol. {137}({1-2}), pp. {3-25} 
    article  
    Abstract: Although the Skinnerian `Empirical Law of Effect' does not directly consider the fundamental properties of stimuli that enable them to act as reinforcers, such considerations are critical for determining if nucleus accumbens dopamine systems mediate reinforcement processes. Researchers who have attempted to identify the critical characteristics of reinforcing stimuli or activities have generally arrived at an emphasis upon motivational factors. A thorough review of the behavioral literature indicates that, across several different investigators offering a multitude of theoretical approaches, motivation is seen by many as being fundamental to the process of reinforcement. The reinforcer has been described as a goal, a commodity, an incentive, or a stimulus that is being approached, self-administered, attained or preserved. Reinforcers also have been described as activities that are preferred, deprived or in some way being regulated. It is evident that this `motivational' or `regulatory' view of reinforcement has had enormous influence over the hypothesis that DA directly mediates `reward' or `reinforcement' processes. Indeed, proponents of the DA/reward hypothesis regularly cite motivational theorists and employ their language. Nevertheless, considerable evidence indicates that low/moderate doses of DA antagonists, and depletions of DA in nucleus accumbens, can suppress instrumental responding for food while, at the same time, these conditions leave fundamental aspects of reinforcement (i.e. primary or unconditioned reinforcement; primary motivation or primary incentive properties of natural reinforcers) intact. Several complex features of the literature on dopaminergic involvement in reinforcement are examined below, and it is argued that the assertions that DA mediates `reward' or `reinforcement' are inaccurate and grossly oversimplified. Thus, it appears as though it is no longer tenable to assert that drugs of abuse are simply turning on the brain's natural `reward system'. In relation to the hypothesis that DA systems are involved in `wanting', but not `liking', it is suggested in the present review that `wanting' has both directional aspects (e.g. appetite to consume food) and activational aspects (e.g. activation for initiating and sustaining instrumental actions; tendency to work for food). The present paper reviews findings in support of the hypothesis that low doses of DA antagonists and accumbens DA depletions do not impair appetite to consume food, but do impair activational aspects of motivation. This suggestion is consistent with the studies showing that low doses of DA antagonists and accumbens DA depletions alter the relative allocation of instrumental responses, making the animals less likely to engage in instrumental responses that have a high degree of work-related response costs. In addition, this observation is consistent with studies demonstrating that accumbens DA depletions make rats highly sensitive to ratio requirements on operant schedules. Although accumbens DA is not seen as directly mediating appetite to consume food, principles of behavioral economics indicate that accumbens DA could be involved in the elasticity of demand for food in terms of the tendency to pay work-related response costs. Future research must focus upon how specific aspects of task requirements (i.e. ratio requirements, intermittence of reinforcement, temporal features of response requirements, dependence upon conditioned stimuli) interact with the effects of accumbens DA depletions, and which particular factors determine sensitivity to the effects of DA antagonism or depletion. (C) 2
    BibTeX:
    @article{Salamone2002,
      author = {Salamone, JD and Correa, M},
      title = {Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {2002},
      volume = {137},
      number = {1-2},
      pages = {3-25}
    }
    
    Salamone, J., Cousins, M. & Snyder, B. Behavioral functions of nucleus accumbens dopamine: Empirical and conceptual problems with the anhedonia hypothesis {1997} NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
    Vol. {21}({3}), pp. {341-359} 
    article  
    Abstract: Nucleus accumbens (DA) has been implicated in a number of different behavioral functions, but most commonly it is said to be involved in `'reward'' or `'reinforcement''. In the present article, the putative reinforcement functions of accumbens DA are summarized in a manner described as the `'General Anhedonia Model''. According to this model, the DA innervation of the nucleus accumbens is conceived of as a crucial link in the `'reward system'', which evolved to mediate the reinforcing effects of natural stimuli such as food. The reward system is said to be activated by natural reinforcing stimuli, and this activation mediates the reinforcing effects of these natural stimuli. According to this view, other stimuli such as brain stimulation and drugs can activate this system, which leads to these stimuli being reinforcing as well. Interference with DA systems is said to blunt the reinforcing effects of these rewarding stimuli, leading to `'extinction''. This general model of the behavioral functions of accumbens DA is utilized widely as a theoretical framework for integrating research findings. Nevertheless, there are several difficulties with the General Anhedonia Model. Several studies have observed substantial differences between the effects of extinction and the effects of DA antagonism or accumbens DA depletions. Studies involving aversive conditions indicate that DA antagonists and accumbens DA depletions can interfere with avoidance behavior, and also have demonstrated that accumbens DA release is increased by stressful or aversive stimuli. Although accumbens DA is important far drug abuse phenomena, particularly stimulant self-administration studies that involve other reinforcers are more problematic. A large body of evidence indicates that low doses of dopamine antagonists, or depletions of accumbens DA, do not impair fundamental aspects of food motivation such as chow consumption and simple instrumental responses for food. This is particularly important, in view of the fact that many behavioral researchers consider the regulation of food motivation to be a fundamental aspect of food reinforcement. Finally, studies employing cost/benefit analyses are reviewed, and in these studies considerable evidence indicates that accumbens DA is involved in the allocation of responses in relation to various reinforcers. Nucleus accumbens DA participates in the function of enabling organisms to overcome response costs, or obstacles, in order to obtain access to stimuli such as food. In summary, nucleus accumbens DA is not seen as directly mediating food reinforcement, but instead is seen as a higher order sensorimotor integrator that is involved in modulating response output in relation to motivational factors and response constraints. Interfering with accumbens DA appears to partially dissociate the process of primary reinforcement from processes regulating instrumental response initiation, maintenance and selection. (C) 1997 Elsevier Science Ltd.
    BibTeX:
    @article{Salamone1997,
      author = {Salamone, JD and Cousins, MS and Snyder, BJ},
      title = {Behavioral functions of nucleus accumbens dopamine: Empirical and conceptual problems with the anhedonia hypothesis},
      journal = {NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS},
      year = {1997},
      volume = {21},
      number = {3},
      pages = {341-359}
    }
    
    Saper, C., Chou, T. & Elmquist, J. The need to feed: Homeostatic and hedonic control of eating {2002} NEURON
    Vol. {36}({2}), pp. {199-211} 
    article  
    Abstract: Feeding provides substrate for energy metabolism, which is vital to the survival of every living animal and therefore is subject to intense regulation by brain homeostatic and hedonic systems. Over the last decade, our understanding of the circuits and molecules involved in this process has changed dramatically, in large part due to the availability of animal models with genetic lesions. In this review, we examine the role played in homeostatic regulation of feeding by systemic mediators such as leptin and ghrelin, which act on brain systems utilizing neuropeptide Y, agouti-related peptide, melanocortins, orexins, and melanin concentrating hormone, among other mediators. We also examine the mechanisms for taste and reward systems that provide food with its intrinsically reinforcing properties and explore the links between the homeostatic and hedonic systems that ensure intake of adequate nutrition.
    BibTeX:
    @article{Saper2002,
      author = {Saper, CB and Chou, TC and Elmquist, JK},
      title = {The need to feed: Homeostatic and hedonic control of eating},
      journal = {NEURON},
      year = {2002},
      volume = {36},
      number = {2},
      pages = {199-211}
    }
    
    Schoemaker, H., Claustre, Y., Fage, D., Rouquier, L., Chergui, K., Curet, O., Oblin, A., Gonon, F., Carter, C., Benavides, J. & Scatton, B. Neurochemical characteristics of amisulpride, an atypical dopamine D-2/D-3 receptor antagonist with both presynaptic and limbic selectivity {1997} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {280}({1}), pp. {83-97} 
    article  
    Abstract: The benzamide derivative amisulpride shows a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effects. In vitro, amisulpride has high affinity and selectivity for the human dopamine D-2 (K-i = 2.8 nM) and D-3 (K-i = 3.2 nM) receptors. Amisulpride shows antagonist properties toward D-3 and both pre- and postsynaptic D-2-like dopamine receptors of the rat striatum or nucleus accumbens in vitro. At low doses (less than or equal to 10 mg/kg) amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D-2 receptor occupancy and antagonism is apparent. In contrast, haloperidol is active in all of these paradigms within the same dose range. Amisulpride preferentially inhibits in vivo binding of the D-2/D-3 antagonist [H-3]raclopride to the limbic system (ID50 = 17 mg/kg) in comparison to the striatum (ID50 = 44 mg/kg) of the rat, increases striatal and limbic tissue 3,4-dihydroxyphenylacetic acid levels with similar potency and efficacy, and preferentially increases extracellular 3,4-dihydroxyphenylacetic acid levels in the nucleus accumbens when compared to the striatum. Haloperidol shows similar potency for the displacement of in vivo [H-3]raclopride binding in striatal and limbic regions and preferentially increases striatal tissue 3,4-dihydroxyphenylacetic acid levels. The present data characterize amisulpride as a specific dopamine receptor antagonist with high and similar affinity for the dopamine D-2 and D-3 receptor. In vivo, it displays a degree of limbic selectivity and a preferential effect, at low doses, on dopamine D-2/D-3 autoreceptors. This atypical profile may explain the therapeutic efficacy of amisulpride in the treatment of both positive and negative symptoms of schizophrenia.
    BibTeX:
    @article{Schoemaker1997,
      author = {Schoemaker, H and Claustre, Y and Fage, D and Rouquier, L and Chergui, K and Curet, O and Oblin, A and Gonon, F and Carter, C and Benavides, J and Scatton, B},
      title = {Neurochemical characteristics of amisulpride, an atypical dopamine D-2/D-3 receptor antagonist with both presynaptic and limbic selectivity},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1997},
      volume = {280},
      number = {1},
      pages = {83-97}
    }
    
    Schultz, W. Getting formal with dopamine and reward {2002} NEURON
    Vol. {36}({2}), pp. {241-263} 
    article  
    Abstract: Recent neurophysiological studies reveal that neurons in certain brain structures carry specific signals about past and future rewards. Dopamine neurons display a short-latency, phasic reward signal indicating the difference between actual and predicted rewards. The signal is useful for enhancing neuronal processing and learning behavioral reactions. It is distinctly different from dopamine's tonic enabling of numerous behavioral processes. Neurons in the striatum, frontal cortex, and amygdala also process reward information but provide more differentiated information for identifying and anticipating rewards and organizing goal-directed behavior. The different reward signals have complementary functions, and the optimal use of rewards in voluntary behavior would benefit from interactions between the signals. Addictive psychostimulant drugs may exert their action by amplifying the dopamine reward signal.
    BibTeX:
    @article{Schultz2002,
      author = {Schultz, W},
      title = {Getting formal with dopamine and reward},
      journal = {NEURON},
      year = {2002},
      volume = {36},
      number = {2},
      pages = {241-263}
    }
    
    Schultz, W. Multiple reward signals in the brain {2000} NATURE REVIEWS NEUROSCIENCE
    Vol. {1}({3}), pp. {199-207} 
    article  
    Abstract: The fundamental biological importance of rewards has created an increasing interest in the neuronal processing of reward information. The suggestion that the mechanisms underlying drug addiction might involve natural reward systems has also stimulated interest. This article focuses on recent neurophysiological studies in primates that have revealed that neurons in a limited number of brain structures carry specific signals about past and future rewards. This research provides the first step towards an understanding of how rewards influence behaviour before they are received and how the brain might use reward information to control learning and goal-directed behaviour.
    BibTeX:
    @article{Schultz2000,
      author = {Schultz, W},
      title = {Multiple reward signals in the brain},
      journal = {NATURE REVIEWS NEUROSCIENCE},
      year = {2000},
      volume = {1},
      number = {3},
      pages = {199-207}
    }
    
    Schultz, W. Predictive reward signal of dopamine neurons {1998} JOURNAL OF NEUROPHYSIOLOGY
    Vol. {80}({1}), pp. {1-27} 
    article  
    Abstract: The effects of lesions, receptor blocking, electrical self-stimulation, and drugs of abuse suggest that midbrain dopamine systems are involved in processing reward information and learning approach behavior. Most dopamine neurons show phasic activations after primary liquid and food rewards and conditioned, reward-predicting visual and auditory stimuli. They show biphasic, activation-depression responses after stimuli that resemble reward-predicting stimuli or are novel or particularly salient. However, only few phasic activations follow aversive stimuli. Thus dopamine neurons label environmental stimuli with appetitive value, predict and detect rewards and signal alerting and motivating events. By failing to discriminate between different rewards, dopamine neurons appear to emit an alerting message about the surprising presence or absence of rewards. All responses to rewards and reward-predicting stimuli depend on event predictability. Dopamine neurons are activated by rewarding events that are better than predicted, remain uninfluenced by events that are as good as predicted, and are depressed by events that are worse than predicted. By signaling rewards according to a prediction error, dopamine responses have the formal characteristics of a teaching signal postulated by reinforcement learning theories. Dopamine responses transfer during learning from primary rewards to reward-predicting stimuli. This may contribute to neuronal mechanisms underlying the retrograde action of rewards, one of the main puzzles in reinforcement learning. The impulse response releases a short pulse of dopamine onto many dendrites, thus broadcasting a rather global reinforcement signal to postsynaptic neurons. This signal may improve approach behavior by providing advance reward information before the behavior occurs, and may contribute to learning by modifying synaptic transmission. The dopamine reward signal is supplemented by activity in neurons in striatum, frontal cortex, and amygdala, which process specific reward information but do not emit a global reward prediction error signal. A cooperation between the different reward signals may assure the use of specific rewards for selectively reinforcing behaviors. Among the other projection systems, noradrenaline neurons predominantly serve attentional mechanisms and nucleus basalis neurons code rewards heterogeneously. Cerebellar climbing fibers signal errors in motor performance or errors in the prediction of aversive events to cerebellar Purkinje cells. Most deficits following dopamine-depleting lesions are not easily explained by a defective reward signal but may reflect the absence of a general enabling function of tonic levels of extracellular dopamine. Thus dopamine systems may have two functions, the phasic transmission of reward information and the tonic enabling of postsynaptic neurons.
    BibTeX:
    @article{Schultz1998,
      author = {Schultz, W},
      title = {Predictive reward signal of dopamine neurons},
      journal = {JOURNAL OF NEUROPHYSIOLOGY},
      year = {1998},
      volume = {80},
      number = {1},
      pages = {1-27}
    }
    
    Schultz, W. Dopamine neurons and their role in reward mechanisms {1997} CURRENT OPINION IN NEUROBIOLOGY
    Vol. {7}({2}), pp. {191-197} 
    article  
    Abstract: Information related to rewards is processed by a limited number of brain structures. Recent studies have demonstrated that dopamine neurons respond to appetitive events, such as primary rewards and reward-predicting stimuli. Rather than responding unconditionally, these neurons signal deviations from the prediction of future appetitive events. These reward-related responses correspond formally to concepts of behavioral and computational learning theories and may thus constitute teaching signals for appetitive learning.
    BibTeX:
    @article{Schultz1997,
      author = {Schultz, W},
      title = {Dopamine neurons and their role in reward mechanisms},
      journal = {CURRENT OPINION IN NEUROBIOLOGY},
      year = {1997},
      volume = {7},
      number = {2},
      pages = {191-197}
    }
    
    Schultz, W., Tremblay, L. & Hollerman, J. Reward processing in primate orbitofrontal cortex and basal ganglia {2000} CEREBRAL CORTEX
    Vol. {10}({3}), pp. {272-283} 
    article  
    Abstract: This article reviews and interprets neuronal activities related to the expectation and delivery of reward in the primate orbitofrontal cortex, in comparison with slowly discharging neurons in the striatum (caudate, putamen and ventral striatum, including nucleus accumbens) and midbrain dopamine neurons. Orbitofrontal neurons showed three principal forms of reward-related activity during the performance of delayed response tasks, namely responses to reward-predicting instructions, activations during the expectation period immediately preceding reward and responses following reward. These activations discriminated between different rewards, often on the basis of the animals' preferences. Neurons in the striatum were also activated in relation to the expectation and detection of reward but in addition showed activities related to the preparation, initiation and execution of movements which reflected the expected reward. Dopamine neurons responded to rewards and reward-predicting stimuli, and coded an error in the prediction of reward. Thus, the investigated cortical and basal ganglia structures showed multiple, heterogeneous, partly simultaneous activations which were related to specific aspects of rewards. These activations may represent the neuronal substrates of rewards during learning and established behavioral performance. The processing of reward expectations suggests an access to central representations of rewards which may be used for the neuronal control of goal-directed behavior.
    BibTeX:
    @article{Schultz2000a,
      author = {Schultz, W and Tremblay, L and Hollerman, JR},
      title = {Reward processing in primate orbitofrontal cortex and basal ganglia},
      journal = {CEREBRAL CORTEX},
      year = {2000},
      volume = {10},
      number = {3},
      pages = {272-283}
    }
    
    Seamans, J., Floresco, S. & Phillips, A. D-1 receptor modulation of hippocampal-prefrontal cortical circuits integrating spatial memory with executive functions in the rat {1998} JOURNAL OF NEUROSCIENCE
    Vol. {18}({4}), pp. {1613-1621} 
    article  
    Abstract: Dopamine (DA) within the prefrontal cortex (PFC) plays an important role in modulating the short-term retention of information during working memory tasks. In contrast, little is known about the role of DA in modulating other executive aspects of working memory such as the use of short-term memory to guide action. The present study examined the effects of D-1 and D-2 receptor blockade in the PFC on foraging by rats on a radial arm maze under two task conditions: (1) a delayed task in which spatial information acquired during a training phase was used 30 min later to guide prospective responses, and (2) a nondelayed task that was identical to the test phase of the delayed task but lacked a training phase, thereby depriving rats of previous information about the location of food on the maze. In experiment 1, microinjections of the D-1 antagonist SCH-23390 (0.05, 0.5, or 5 mu g/mu l), but not the D-2 anatagonist sulpiride (0.05, 0.5, or 5 mu g/mu l), into the prelimbic region of the PFC before the test phase disrupted performance of the delayed task without affecting response latencies. In contrast, neither drug affected performance of the nondelayed task. In the present study, we also investigated the role of D-1 receptors in modulating activity in hippocampal-PFC circuits during delayed responding. Unilateral injections of SCH-23390 into the PFC in the hemisphere contralateral to a microinjection of lidocaine into the hippocampus severely disrupted performance of the delayed task. Thus, the ability to use previously acquired spatial information to guide responding 30 min later on a radial arm maze requires D-1 receptor activation in the PFC and D-1 receptor modulation of hippocampal inputs to the PFC. These data suggest that D-1 receptors in the PFC are involved in working memory processes other than just the short-term active retention of information and also provide direct evidence for DA modulation of limbic-PFC circuits during behavior.
    BibTeX:
    @article{Seamans1998,
      author = {Seamans, JK and Floresco, SB and Phillips, AG},
      title = {D-1 receptor modulation of hippocampal-prefrontal cortical circuits integrating spatial memory with executive functions in the rat},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1998},
      volume = {18},
      number = {4},
      pages = {1613-1621}
    }
    
    Seamans, J. & Yang, C. The principal features and mechanisms of dopamine modulation in the prefrontal cortex {2004} PROGRESS IN NEUROBIOLOGY
    Vol. {74}({1}), pp. {1-57} 
    article DOI  
    Abstract: Mesocotical dopamine (DA) inputs to the prefrontal cortex (PFC) play a crtical role in normal cognitive process and neuropsychiatic pathologies. This DA input regulates aspects of working memory function, planning and attention, and its dysfunctions may underlie positive and negative symtoms and cognitive deficits associated with schizophrenia. Despite intense research, there is still a lack of clear understanding of the basic principles of actions of DA in the PFC. In recent years, there has been considerable efforts by many groups to understand the cellular mechanisms of DA modulation of PFC neurons. However, the results of these efforts often lead to contradictions and controversies. One principal feature of DA that is agreed by most researchers is that DA is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter. The present article aims to identify certain principles of DA mechanisms by drawing on published, as well as unpublished data from PFC and other CNS sites to shed light on aspects of DA neuromodulation and address some of the existing controversies. Eighteen key features about DA modulation have been identified. These points directly impact on the end result of DA neuromodulation, and in some cases explain why DA does not yield identical effects under all experimental conditions. It will become apparent that DA's actions in PFC are subtle and depend on a variety of factors that can no longer be ignored. Some of these key factors include distinct bell-shaped dose-response profiles of postsynaptic DA effects, different postsynaptic responses that are contingent on the duration of DA receptor stimulation, prolonged duration effects, bidirectional effects following activation of D1 and D2 classes of receptors and membrane potential state and history dependence of subsequent DA actions. It is hoped that these factors will be borne in mind in future research and as a result a more consistent picture of DA neuromodulation in the PFC will emerge. Based on these factors, a theory is proposed for DA's action in PFC. This theory suggests that DA acts to expand or contract the breadth of information held in working memory buffers in PFC networks. (C) 2004 Elsevier Ltd. All rights reserved.
    BibTeX:
    @article{Seamans2004,
      author = {Seamans, JK and Yang, CR},
      title = {The principal features and mechanisms of dopamine modulation in the prefrontal cortex},
      journal = {PROGRESS IN NEUROBIOLOGY},
      year = {2004},
      volume = {74},
      number = {1},
      pages = {1-57},
      doi = {{10.1016/j.pneurobio.2004.05.006}}
    }
    
    SEGAL, D. & KUCZENSKI, R. INVIVO MICRODIALYSIS REVEALS A DIMINISHED AMPHETAMINE-INDUCED DA RESPONSE CORRESPONDING TO BEHAVIORAL SENSITIZATION PRODUCED BY REPEATED AMPHETAMINE PRETREATMENT {1992} BRAIN RESEARCH
    Vol. {571}({2}), pp. {330-337} 
    article  
    Abstract: In vivo microdialysis procedures were used to assess the effects of repeated amphetamine administration on behavior and regional brain DA dynamics in freely moving rats. Pretreatment with amphetamine (2.5 or 3.0 mg/kg) for 4-6 days did not alter baseline DA or its metabolites in caudate or accumbens 48 h or 6 days after the last injection. However, whereas this dosage regimen revealed a profound behavioral sensitization in response to challenge with amphetamine (2.5 mg/kg), including a more rapid onset and intensification of stereotypy, the DA response was significantly diminished in both brain regions. In addition, the ratio of caudate to accumbens DA, either before or after amphetamine challenge, was not altered by the pretreatment regimen. These results are consistent with our previous suggestion that there is a dissociation between the DA and behavioral responses to amphetamine, and therefore that other neurotransmitter systems and/or mechanisms significantly contribute to the amphetamine response profile. Furthermore, DA effects may represent only one, albeit critical aspect in a time-dependent sequence of changes underlying stimulant sensitization.
    BibTeX:
    @article{SEGAL1992,
      author = {SEGAL, DS and KUCZENSKI, R},
      title = {INVIVO MICRODIALYSIS REVEALS A DIMINISHED AMPHETAMINE-INDUCED DA RESPONSE CORRESPONDING TO BEHAVIORAL SENSITIZATION PRODUCED BY REPEATED AMPHETAMINE PRETREATMENT},
      journal = {BRAIN RESEARCH},
      year = {1992},
      volume = {571},
      number = {2},
      pages = {330-337}
    }
    
    SEIDEN, L. & SABOL, K. AMPHETAMINE - EFFECTS ON CATECHOLAMINE SYSTEMS AND BEHAVIOR {1993} ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY
    Vol. {33}, pp. {639-677} 
    article  
    BibTeX:
    @article{SEIDEN1993,
      author = {SEIDEN, LS and SABOL, KE},
      title = {AMPHETAMINE - EFFECTS ON CATECHOLAMINE SYSTEMS AND BEHAVIOR},
      journal = {ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY},
      year = {1993},
      volume = {33},
      pages = {639-677}
    }
    
    Self, D., Genova, L., Hope, B., Barnhart, W., Spencer, J. & Nestler, E. Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior {1998} JOURNAL OF NEUROSCIENCE
    Vol. {18}({5}), pp. {1848-1859} 
    article  
    Abstract: cAMP-dependent protein kinase (PKA) in the nucleus accumbens (NAc) has been implicated in cocaine addiction because (1) cocaine reinforcement is mediated by dopamine receptors that modulate cAMP formation, and (2) repeated exposure to cocaine upregulates the cAMP system in NAc neurons. This study tested PKA involvement in cocaine self-administration and relapse of cocaine-seeking behavior by infusing cAMP analogs that activate or inhibit PKA into the NAc of rats. Bilateral intra-NAc infusions of the PKA inhibitor R-p-cAMPS reduced baseline cocaine self-administration, shifted the dose-response curve for cocaine self-administration to the left, and induced relapse of cocaine-seeking behavior after extinction from cocaine self-administration, consistent with an enhancement of cocaine effects in each paradigm. In contrast, pretreatment with intra-NAc infusions of a PKA activator, S-p-cAMPS or dibutyryl cAMP, increased baseline cocaine self-administration during the second hour of testing and shifted the dose-response curve to the right, consistent with an antagonist-like action. After extinction from cocaine self-administration, similar infusions of Sp-cAMPS induced generalized responding at both drug-paired and inactive levers. As an index of PKA activity in vivo, NAc infusions of Rp-cAMPS reduced basal levels of dopamine-regulated phosphoprotein-32 phosphorylation and blocked amphetamine-induced increases in cAMP response element-binding protein (CREB) phosphorylation. Conversely, NAc infusions of S-p-cAMPS increased phosphorylation of CREB. Together, these results suggest that sustained upregulation of the cAMP system in the NAc after repeated cocaine exposure could underlie tolerance to cocaine reinforcement, whereas acute inhibition of this system may contribute to drug craving and relapse in addicted subjects.
    BibTeX:
    @article{Self1998,
      author = {Self, DW and Genova, LM and Hope, BT and Barnhart, WJ and Spencer, JJ and Nestler, EJ},
      title = {Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1998},
      volume = {18},
      number = {5},
      pages = {1848-1859}
    }
    
    SELF, D. & NESTLER, E. MOLECULAR MECHANISMS OF DRUG REINFORCEMENT AND ADDICTION {1995} ANNUAL REVIEW OF NEUROSCIENCE
    Vol. {18}, pp. {463-495} 
    article  
    BibTeX:
    @article{SELF1995,
      author = {SELF, DW and NESTLER, EJ},
      title = {MOLECULAR MECHANISMS OF DRUG REINFORCEMENT AND ADDICTION},
      journal = {ANNUAL REVIEW OF NEUROSCIENCE},
      year = {1995},
      volume = {18},
      pages = {463-495}
    }
    
    SELLERS, E., HIGGINS, G. & SOBELL, M. 5-HT AND ALCOHOL-ABUSE {1992} TRENDS IN PHARMACOLOGICAL SCIENCES
    Vol. {13}({2}), pp. {69-75} 
    article  
    Abstract: Recent experimental data, both in animals and the clinic, suggest that drugs selectively interacting with the 5-HT system may reduce alcohol intake. Although the precise mechanisms underlying these drug effects are unknown, it seems that there are at least two pharmacological strategies available, described in this review by Edward Sellers and colleagues. The first is enhancement of 5-HT neuronal activity using compounds that will release 5-HT, block 5-HT reuptake, or act as selective 5-HT receptor agonists. A second approach involves selective 5-HT3 receptor antagonists. If the initial research findings with these drugs are confirmed and extended, they may present useful therapies for the treatment of alcohol abuse, especially if used in conjunction with psychosocial therapy.
    BibTeX:
    @article{SELLERS1992,
      author = {SELLERS, EM and HIGGINS, GA and SOBELL, MB},
      title = {5-HT AND ALCOHOL-ABUSE},
      journal = {TRENDS IN PHARMACOLOGICAL SCIENCES},
      year = {1992},
      volume = {13},
      number = {2},
      pages = {69-75}
    }
    
    SESACK, S., AOKI, C. & PICKEL, V. ULTRASTRUCTURAL-LOCALIZATION OF D-2 RECEPTOR-LIKE IMMUNOREACTIVITY IN MIDBRAIN DOPAMINE NEURONS AND THEIR STRIATAL TARGETS {1994} JOURNAL OF NEUROSCIENCE
    Vol. {14}({1}), pp. {88-106} 
    article  
    Abstract: Potential cellular substrates for functions ascribed to the dopamine D-2 receptor were examined in rat brain using immunoperoxidase for localization of a D-2 receptor peptide and immunogold staining for the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH). Specificity of the rat polyclonal antiserum, raised against a 15 amino acid fragment from the third intracellular loop of the D-2 receptor, was shown by immunoblot analysis and by selective labeling of cultured Chinese hamster ovary cells permanently transfected with the cDNA for the D-2 receptor. Although the light microscopic distribution of immunolabeling for the D-2 peptide was diffuse, it was selectively localized to regions containing dopamine cells (substantia nigra and ventral tegmental area) or their forebrain projections (dorsal and ventral striatum, nucleus accumbens, and olfactory tubercles). Electron microscopic examination of the medial substantia nigra and ventral tegmental area revealed readily detectable peroxidase immunoreactivity for the D-2 peptide, primarily associated with the smooth endoplasmic reticulum and plasmalemmal surfaces of dendrites. Many D-2 peptide-immunoreactive dendrites also contained immunogold labeling for TH, although some dendrites were singly labeled for either marker. In the medial and dorsolateral striatum, immunoperoxidase product for the D-2 peptide was localized most extensively in dendrites, with the greatest intensity of immunolabeling seen in spines. A number of striatal dendrites exhibiting D-2 peptide labeling were contacted by axon terminals immunoreactive for TH. Additionally, D-2 peptide immunoreactivity was distributed to some synaptic vesicles and portions of the plasmalemmal surface in unmyelinated axons and in axon terminals. Most D-2 peptide-immunoreactive terminals either lacked detectable membrane specializations, or formed thin, symmetric synapses in single sections. A few D-2 peptide-labeled terminals formed asymmetric junctions on dendritic spines. In dually labeled sections, most D-2 peptide-immunoreactive terminals lacked detectable immunolabeling for TH. However, in fortunate planes of section, peroxidase product for D-2 peptide immunoreactivity was occasionally seen in preterminal portions of axons whose terminal varicosities contained immunogold labeling for TH. These ultrastructural results are consistent with the localization of a dopamine D-2 receptor-like protein that is strategically positioned to subserve (1) autoreceptor functions at the level of dendrites in the midbrain and presynaptic axon terminals in the striatum, as well as (2) postsynaptic actions on striatal spiny dendrites and other nondopamine terminals.
    BibTeX:
    @article{SESACK1994,
      author = {SESACK, SR and AOKI, C and PICKEL, VM},
      title = {ULTRASTRUCTURAL-LOCALIZATION OF D-2 RECEPTOR-LIKE IMMUNOREACTIVITY IN MIDBRAIN DOPAMINE NEURONS AND THEIR STRIATAL TARGETS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1994},
      volume = {14},
      number = {1},
      pages = {88-106}
    }
    
    Sesack, S., Hawrylak, V., Matus, C., Guido, M. & Levey, A. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter {1998} JOURNAL OF NEUROSCIENCE
    Vol. {18}({7}), pp. {2697-2708} 
    article  
    Abstract: The dopamine transporter (DAT) critically regulates the duration of the cellular actions of dopamine and the extent to which dopamine diffuses in the extracellular space. We sought to determine whether the reported ly greater diffusion of dopamine in the rat prefrontal cortex (PFC) as compared with the striatum is associated with a more restricted axonal distribution of the cortical DAT protein. By light microscopy, avidin-biotin-peroxidase immunostaining for DAT was visualized in fibers that were densely distributed within the dorsolateral striatum and the superficial layers of the dorsal anterior cingulate cortex. In contrast, DAT-labeled axons were distributed only sparsely to the deep layers of the prelimbic cortex. By electron microscopy, DAT-immunoreactive profiles in the striatum and cingulate cortex included both varicose and intervaricose segments of axons. However, DAT-labeled processes in the prelimbic cortex were almost exclusively intervaricose axon segments. Immunolabeling for tyrosine hydroxylase in adjacent sections of the prelimbic cortex was localized to both varicosities and intervaricose segments of axons. These qualitative observations were supported by a quantitative assessment in which the diameter of immunoreactive profiles was used as a relative measure of whether varicose or intervaricose axon segments were labeled. These results suggest that considerable extracellular diffusion of dopamine in the prelimbic PFC may result, at least in part, from a paucity of DAT content in mesocortical dopamine axons, as well as a distribution of the DAT protein at a distance from synaptic release sites. The results further suggest that different populations of dopamine neurons selectively target the DAT to different subcellular locations.
    BibTeX:
    @article{Sesack1998,
      author = {Sesack, SR and Hawrylak, VA and Matus, C and Guido, MA and Levey, AI},
      title = {Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1998},
      volume = {18},
      number = {7},
      pages = {2697-2708}
    }
    
    SESACK, S. & PICKEL, V. PREFRONTAL CORTICAL EFFERENTS IN THE RAT SYNAPSE ON UNLABELED NEURONAL TARGETS OF CATECHOLAMINE TERMINALS IN THE NUCLEUS-ACCUMBENS-SEPTI AND ON DOPAMINE NEURONS IN THE VENTRAL TEGMENTAL AREA {1992} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {320}({2}), pp. {145-160} 
    article  
    Abstract: Physiological and pharmacological studies indicate that descending projections from the prefrontal cortex modulate dopaminergic transmission in the nucleus accumbens septi and ventral tegmental area. We investigated the ultrastructural bases for these interactions in rat by examining the synaptic associations between prefrontal cortical terminals labeled with anterograde markers (lesion-induced degeneration or transport of Phaseolus vulgaris leucoag-glutinin; PHA-L) and neuronal processes containing immunoreactivity for the catecholamine synthesizing enzyme, tryosine hydroxylase. Prefrontal cortical terminals in the nucleus accumbens and ventral tegmental area contained clear, round vesicles and formed primarily asymmetric synapses on spines or small dendrites. In the ventral tegmental area, these terminals also formed asymmetric synapses on large dendrites and a few symmetric axodendritic synapses. In the nucleus accumbens septi, degenerating prefrontal cortical terminals synapsed on spiny dendrites which received convergent input from terminals containing peroxidase immunoreactivity for tyrosine hydroxylase, or from unlabeled terminals. In single sections, some tyrosine hydroxylase-labeled terminals formed thin and punctate symmetric synapses with dendritic shafts, or the heads and necks of spines. Close appositions, but not axo-axonic synapses, were frequently observed between degenerating prefrontal cortical afferents and tyrosine hydroxylase-labeled or unlabeled terminals. In the ventral tegmental area, prefrontal cortical terminals labeled with immunoperoxidase for PHA-L were in synaptic contact with dendrites containing immunogold reaction product for tyrosine hydroxylase, or with unlabeled dendrites. These results suggest that: (1) catecholaminergic (mainly dopaminergic) and prefrontal cortical terminals in the nucleus accumbens septi dually synapse on common spiny neurons; and (2) dopaminergic neurons in the ventral tegmental area receive monosynaptic input from prefrontal cortical afferents. This study provides the first ultrastructural basis for multiple sites of cellular interaction between prefrontal cortical efferents and mesolimbic dopaminergic neurons.
    BibTeX:
    @article{SESACK1992,
      author = {SESACK, SR and PICKEL, VM},
      title = {PREFRONTAL CORTICAL EFFERENTS IN THE RAT SYNAPSE ON UNLABELED NEURONAL TARGETS OF CATECHOLAMINE TERMINALS IN THE NUCLEUS-ACCUMBENS-SEPTI AND ON DOPAMINE NEURONS IN THE VENTRAL TEGMENTAL AREA},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1992},
      volume = {320},
      number = {2},
      pages = {145-160}
    }
    
    SESACK, S. & PICKEL, V. IN THE RAT MEDIAL NUCLEUS-ACCUMBENS, HIPPOCAMPAL AND CATECHOLAMINERGIC TERMINALS CONVERGE ON SPINY NEURONS AND ARE IN APPOSITION TO EACH OTHER {1990} BRAIN RESEARCH
    Vol. {527}({2}), pp. {266-279} 
    article  
    BibTeX:
    @article{SESACK1990,
      author = {SESACK, SR and PICKEL, VM},
      title = {IN THE RAT MEDIAL NUCLEUS-ACCUMBENS, HIPPOCAMPAL AND CATECHOLAMINERGIC TERMINALS CONVERGE ON SPINY NEURONS AND ARE IN APPOSITION TO EACH OTHER},
      journal = {BRAIN RESEARCH},
      year = {1990},
      volume = {527},
      number = {2},
      pages = {266-279}
    }
    
    Shaham, Y., Erb, S. & Stewart, J. Stress-induced relapse to heroin and cocaine seeking in rats: a review {2000} BRAIN RESEARCH REVIEWS
    Vol. {33}({1}), pp. {13-33} 
    article  
    Abstract: Studies in humans suggest that exposure to stress increases the probability of relapse to drug use, bur until recently there has been no animal model to study the mechanisms that mediate this effect. We have developed a reinstatement procedure that allows us to study the effect of stress on relapse to drug seeking in rats. Using this procedure, we have shown that exposure to intermittent footshock stress reliably reinstates heroin and cocaine seeking after prolonged drug-free periods. In the present paper, we summarize results from several studies on stress-induced reinstatement of heroin and cocaine seeking in rats. We first assess the degree to which the phenomenon of stress-induced relapse generalizes to other stressors, to behaviors controlled by other drugs of abuse, and to behaviors controlled by non-drug reinforcers. We then review evidence from studies concerned with the neurotransmitters, the brain sites, and the neural systems involved in stress-induced reinstatement of drug seeking. Finally, we consider the mechanisms that might underlie stress-induced relapse to drug seeking and the possible implications of the findings for the treatment of relapse to drug use in humans. (C) 2000 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{Shaham2000,
      author = {Shaham, Y and Erb, S and Stewart, J},
      title = {Stress-induced relapse to heroin and cocaine seeking in rats: a review},
      journal = {BRAIN RESEARCH REVIEWS},
      year = {2000},
      volume = {33},
      number = {1},
      pages = {13-33}
    }
    
    Shaham, Y., Shalev, U., Lu, L., de Wit, H. & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings {2003} PSYCHOPHARMACOLOGY
    Vol. {168}({1-2}), pp. {3-20} 
    article DOI  
    Abstract: Rational and objectives.. The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. Conclusions.. The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.
    BibTeX:
    @article{Shaham2003,
      author = {Shaham, Y and Shalev, U and Lu, L and de Wit, H and Stewart, J},
      title = {The reinstatement model of drug relapse: history, methodology and major findings},
      journal = {PSYCHOPHARMACOLOGY},
      year = {2003},
      volume = {168},
      number = {1-2},
      pages = {3-20},
      doi = {{10.1007/s00213-002-1224-x}}
    }
    
    SHAHAM, Y. & STEWART, J. STRESS REINSTATES HEROIN-SEEKING IN DRUG-FREE ANIMALS - AN EFFECT MIMICKING HEROIN, NOT WITHDRAWAL {1995} PSYCHOPHARMACOLOGY
    Vol. {119}({3}), pp. {334-341} 
    article  
    Abstract: Exposure to 10 min of footshock stress (1 mA; 0.5 s on, with a mean off period of 40 s) reinstated heroin-seeking behavior in heroin-experienced, drug-free rats after many sessions of extinction and up to 6 weeks after last exposure to heroin. In reinstating the behavior, the footshock mimicked the effect of a non-contingent priming infusion of heroin (50 mu g/kg). By contrast, the aversive state of acute opioid withdrawal induced by injection of the opioid receptor antagonist naltrexone (5 mg/kg, SC), following an acute injection of morphine (10 mg/kg, SC), had no effect on heroin-seeking behavior. In a second experiment it was shown in drug naive animals that these parameters of footshock increased dopamine overflow in the nucleus accumbens, a terminal region of the mesolimbic dopamine system implicated in the reinforcing effects of drugs. Similarly, dopamine overflow was increased by an injection of 10 mg/kg morphine, SC, an effect that was reversed by an injection of 5 mg/kg naltrexone given 40 min after to induce the withdrawal condition. A possible interpretation of the present results is that stressors can reinstate drug-taking behavior by activating neural systems in common with those activated by heroin.
    BibTeX:
    @article{SHAHAM1995,
      author = {SHAHAM, Y and STEWART, J},
      title = {STRESS REINSTATES HEROIN-SEEKING IN DRUG-FREE ANIMALS - AN EFFECT MIMICKING HEROIN, NOT WITHDRAWAL},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1995},
      volume = {119},
      number = {3},
      pages = {334-341}
    }
    
    Shalev, U., Grimm, J. & Shaham, Y. Neurobiology of relapse to heroin and cocaine seeking: A review {2002} PHARMACOLOGICAL REVIEWS
    Vol. {54}({1}), pp. {1-42} 
    article  
    Abstract: The objective of this article is to review data from studies that used a reinstatement model in rats to elucidate the neural mechanisms underlying relapse to heroin and cocaine seeking induced by exposure to the self-administered drug (drug priming), conditioned drug cues, and stressors. These factors were reported to contribute to relapse to drug use in humans following prolonged abstinence periods. In the reinstatement model, the ability of acute exposure to drug or nondrug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies in which pharmacological agents were injected systemically or intracranially to block (or mimic) reinstatement by drug priming, drug cues, and stressors. We also will review studies in which brain lesions, in vivo microdialysis and electrochemistry, and gene expression methods were used to map brain sites involved in relapse to drug seeking. Subsequently, we will discuss theoretical issues related to the processes underlying relapse to drugs and address methodological issues in studies on reinstatement of drug seeking. Finally, the implications of the findings from the studies reviewed for addiction theories and treatment will be discussed. The main conclusion of this review is that the neuronal mechanisms involved in relapse to heroin and cocaine seeking induced by drug priming, drug cues, and stressors are to a large degree dissociable. The data reviewed also suggest that the neuronal events mediating drug-induced reinstatement are to some degree dissociable from those mediating drug reinforcement.
    BibTeX:
    @article{Shalev2002,
      author = {Shalev, U and Grimm, JW and Shaham, Y},
      title = {Neurobiology of relapse to heroin and cocaine seeking: A review},
      journal = {PHARMACOLOGICAL REVIEWS},
      year = {2002},
      volume = {54},
      number = {1},
      pages = {1-42}
    }
    
    SHIGEMOTO, R., NOMURA, S., OHISHI, H., SUGIHARA, H., NAKANISHI, S. & MIZUNO, N. IMMUNOHISTOCHEMICAL LOCALIZATION OF A METABOTROPIC GLUTAMATE-RECEPTOR, MGLUR5, IN THE RAT-BRAIN {1993} NEUROSCIENCE LETTERS
    Vol. {163}({1}), pp. {53-57} 
    article  
    Abstract: A trpE-fusion protein containing a C-terminal sequence of a rat metabotropic glutamate receptor, mGluR5, was used to produce an antibody. On immunoblot, the antibody specifically reacted with mGluR5 expressed in mammalian cells and rat brain. Immunohistochemical analysis revealed intense mGluR5-like immunoreactivity (LI) in the olfactory bulb, anterior olfactory nuclei, olfactory tubercle, cerebral cortex, hippocampus, lateral septum, striatum, nucleus accumbens, inferior colliculus, and spinal trigeminal nuclei. The distribution pattern of mGluR5-LI corresponds very well with that of mGluR5 mRNA. Electron microscope analysis of the striatum revealed dense accumulation of immunoreaction products in dendrites which were often provided with asymmetrical synapses. These results suggest that mGluR5 is predominantly located in postsynaptic elements.
    BibTeX:
    @article{SHIGEMOTO1993,
      author = {SHIGEMOTO, R and NOMURA, S and OHISHI, H and SUGIHARA, H and NAKANISHI, S and MIZUNO, N},
      title = {IMMUNOHISTOCHEMICAL LOCALIZATION OF A METABOTROPIC GLUTAMATE-RECEPTOR, MGLUR5, IN THE RAT-BRAIN},
      journal = {NEUROSCIENCE LETTERS},
      year = {1993},
      volume = {163},
      number = {1},
      pages = {53-57}
    }
    
    SHIPPENBERG, T., BALSKUBIK, R. & HERZ, A. EXAMINATION OF THE NEUROCHEMICAL SUBSTRATES MEDIATING THE MOTIVATIONAL EFFECTS OF OPIOIDS - ROLE OF THE MESOLIMBIC DOPAMINE SYSTEM AND D-1 VS D-2 DOPAMINE-RECEPTORS {1993} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {265}({1}), pp. {53-59} 
    article  
    Abstract: Both the reinforcing and aversive effects of exogenous opioids have been attributed to the activation of opioid receptors within the mesolimbic dopamine (DA) system. At present, however, it is unclear whether the activity of DA neurons projecting to the nucleus accumbens (NAC) is necessary for the expression of these effects. The present study sought to address this issue in rats by examining the influence of 6-hydroxydopamine (6-OHDA) lesions of the NAC and microinjections of selective DA receptor antagonists into this brain area upon the place conditioning produced by systemically administered opioids. The mu-opioid receptor agonist morphine produced dose-related preferences for the drug-paired place in control animals, whereas the kappa-opioid agonist U-69593 produced place aversions. Bilateral 6-OHDA lesions of the NAC abolished the place conditioning produced by both opioids. Lesions of the caudate/putamen or medial prefrontal cortex were, however, without effect. Microinjection of the D-1 DA antagonist SCH-23390 into the NAC, at a dose which was as ineffective as a conditioning stimulus, attenuated the place conditioning produced by low doses of morphine and U-69593. Over the dose range tested, the D-2 DA antagonist (-)-sulpiride was without effect. Neither SCH-23390 nor 6-OHDA lesions of the NAC modified the place conditioning produced by lithium chloride, a drug of a different pharmacological class. These data demonstrate that the rewarding and aversive effects of opioids are dependent on DA neural transmission within the mesolimbic system and suggest a role for NAC D-1 DA receptors in the mediation of both motivational effects.
    BibTeX:
    @article{SHIPPENBERG1993,
      author = {SHIPPENBERG, TS and BALSKUBIK, R and HERZ, A},
      title = {EXAMINATION OF THE NEUROCHEMICAL SUBSTRATES MEDIATING THE MOTIVATIONAL EFFECTS OF OPIOIDS - ROLE OF THE MESOLIMBIC DOPAMINE SYSTEM AND D-1 VS D-2 DOPAMINE-RECEPTORS},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1993},
      volume = {265},
      number = {1},
      pages = {53-59}
    }
    
    SHIPPENBERG, T. & HEIDBREDER, C. SENSITIZATION TO THE CONDITIONED REWARDING EFFECTS OF COCAINE - PHARMACOLOGICAL AND TEMPORAL CHARACTERISTICS {1995} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {273}({2}), pp. {808-815} 
    article  
    Abstract: An unbiased place preference conditioning procedure was used to determine whether the repeated administration of cocaine results in sensitization to its conditioned rewarding effects. Rats received noncontingent injections of saline or cocaine (10 mg/kg i.p.) for 5 days. Place preference conditioning commenced 72 hr later. A minimum of three drug conditioning sessions was necessary for the establishment of cocaine-induced conditioned place preferences (CPP) in saline-pretreated rats. The minimum dose producing this effect was 10.0 mg/kg. In contrast, pre-exposure to cocaine resulted in significant place preferences occurring after only two drug conditioning sessions. Furthermore, CPP was observed in response to doses as low as 5.0 mg/kg. This shift in the cocaine dose-response curve was apparent when conditioning commenced either 3 or 7, but not 14, days after the cessation of cocaine pretreatment. An increased sensitivity to cocaine was also observed in rats which received only two cocaine (25.0 mg/kg) injections before conditioning and in those which had received either d-amphetamine (0.5 mg/kg) or morphine (5.0 mg/kg) for 5 days. Repeated administration of the D1 dopamine (DA) receptor antagonist, SCH-23390 (0.01-0.05 mg/kg), or the D2 antagonist, raclopride (0.1-1.0 mg/kg), for 5 days did not modify cocaine-induced place conditioning. Administration of SCH-23390 (0.05 mg/kg) in combination with cocaine, however, prevented the sensitized response to cocaine. In contrast, raclopride did not influence the sensitized response to cocaine. These data demonstrate that sensitization occurs to the conditioned rewarding effects of cocaine and suggest an involvement of D1 DA receptors in the development of this phenomenon.
    BibTeX:
    @article{SHIPPENBERG1995,
      author = {SHIPPENBERG, TS and HEIDBREDER, C},
      title = {SENSITIZATION TO THE CONDITIONED REWARDING EFFECTS OF COCAINE - PHARMACOLOGICAL AND TEMPORAL CHARACTERISTICS},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1995},
      volume = {273},
      number = {2},
      pages = {808-815}
    }
    
    Sinha, R. How does stress increase risk of drug abuse and relapse? {2001} PSYCHOPHARMACOLOGY
    Vol. {158}({4}), pp. {343-359} 
    article DOI  
    Abstract: Rationale: The notion that stress leads to drug abuse in vulnerable individuals and relapse in addicts is not new. Most major theories of addiction postulate that stress plays an important role in increasing drug use and relapse. Several animal studies and some human laboratory studies have shown that stress exposure enhances drug self-administration. Although clinical observations suggest that exposure to stress increases drug use, and are associated with craving and relapse in addicts, human research in this area is largely correlational and at times contradictory. Objective: Given the growing preclinical evidence that supports the key role of stress in substance abuse, careful examination of this research area in humans is warranted. This paper examines empirical evidence on how stress may increase the vulnerability to drug abuse, and explores whether chronic drug abuse alters the stress response and coping in addicts, thereby increasing the likelihood of drug seeking and relapse. Unanswered questions on the association between stress and substance abuse in humans are identified. Conclusion: Preclinical research has shown that stress, in addition to drug itself, plays a key role in perpetuating drug abuse and relapse. However, the mechanisms underlying this association in humans remain unclear. A greater understanding of how stress may perpetuate drug abuse will likely have a significant impact on both prevention and treatment development in the field of addiction.
    BibTeX:
    @article{Sinha2001,
      author = {Sinha, R},
      title = {How does stress increase risk of drug abuse and relapse?},
      journal = {PSYCHOPHARMACOLOGY},
      year = {2001},
      volume = {158},
      number = {4},
      pages = {343-359},
      doi = {{10.1007/s002130100917}}
    }
    
    Snyder, G., Fienberg, A., Huganir, R. & Greengard, P. A dopamine D1 receptor protein kinase A dopamine- and cAMP-regulated phosphoprotein (M-r 32 kDa) protein phosphatase-1 pathway regulates dephosphorylation of the NMDA receptor {1998} JOURNAL OF NEUROSCIENCE
    Vol. {18}({24}), pp. {10297-10303} 
    article  
    Abstract: We have investigated the mechanism by which activation of dopamine (DA) receptors regulates the glutamate sensitivity of medium spiny neurons of the nucleus accumbens. Our results demonstrate that DA regulates the phosphorylation state of the NR1 subunit of NMDA-type glutamate receptors. The effect of DA was mimicked by SKF82526, a D1-type DA receptor agonist, and by forskolin, an activator of cAMP-dependent protein kinase (PKA), and was blocked by H-89, a PKA inhibitor. These data indicate that DA increases NR1 phosphorylation through a PKA-dependent pathway. DA-induced phosphorylation of NR1 was blocked in mice bearing a targeted deletion of the gene for dopamine- and cAMP-regulated phosphoprotein of M-r 32 kDa (DARPP-32), a phosphoprotein that is a potent and selective inhibitor of protein phosphatase-l, indicating that the effect of PKA is mediated, in part, by regulation of the DARPP-32/protein phosphatase-l cascade. In support of this interpretation, NR1 phosphorylation was increased by calyculin A, a protein phosphatase-1/2A inhibitor. A model is proposed in which the ability of DA to regulate NMDA receptor sensitivity is attributable to a synergistic action involving increased phosphorylation and decreased dephosphorylation of the NR1 subunit of the NMDA receptor.
    BibTeX:
    @article{Snyder1998,
      author = {Snyder, GL and Fienberg, AA and Huganir, RL and Greengard, P},
      title = {A dopamine D1 receptor protein kinase A dopamine- and cAMP-regulated phosphoprotein (M-r 32 kDa) protein phosphatase-1 pathway regulates dephosphorylation of the NMDA receptor},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1998},
      volume = {18},
      number = {24},
      pages = {10297-10303}
    }
    
    SOBREVIELA, T., CLARY, D., REICHARDT, L., BRANDABUR, M., KORDOWER, J. & MUFSON, E. TRKA-IMMUNOREACTIVE PROFILES IN THE CENTRAL-NERVOUS-SYSTEM - COLOCALIZATION WITH NEURONS CONTAINING P75 NERVE GROWTH-FACTOR RECEPTOR, CHOLINE-ACETYLTRANSFERASE, AND SEROTONIN {1994} JOURNAL OF COMPARATIVE NEUROLOGY
    Vol. {350}({4}), pp. {587-611} 
    article  
    Abstract: The present investigation used an antibody directed against the extracellular domain of the signal transducing nerve growth factor receptor, trkA, to reveal immunoreactive perikarya or fibers within the olfactory bulb and tubercle, cingulate cortex, nucleus accumbens, striatum, endopiriform nucleus, septal/diagonal band complex, nucleus basalis, hippocampal complex, thalamic paraventricular and reuniens nuclei, periventricular hypothalamus, interpeduncular nucleus, mesencephalic nucleus of the fifth nerve, dorsal nucleus of the lateral lemniscus, prepositus hypoglossal nucleus, ventral cochlear nucleus, ventral lateral tegmentum, medial vestibular nucleus, spinal trigeminal nucleus oralis, nucleus of the solitary tract, raphe nuclei, and spinal cord. Colocalization experiments revealed that virtually all striatal trkA-immunoreactive neurons (>99 coexpressed choline acetyltransferase (ChAT) but not p75 nerve growth factor receptor (NGFR). Within the septal/diagonal band complex virtually all trkA neurons (>95 coexpressed both ChAT and p75 NGFR. More caudally, dual stained sections revealed numerous trkA/ChAT (>80 and trkA/p75 NGFR (>95 immunoreactive neurons within the nucleus basalis. In the brainstem, raphe serotonergic neurons (45 coexpressed trkA. Sections stained with a pan-trk antibody that recognizes primarily trkA, as well as trkB and trkC, labeled neurons within all of these regions as well as within the hypothalamic arcuate, supramammilary, and supraoptic nuclei, hippocampus, inferior and superior colliculus, substantia nigra, ventral tegmental area of T'sai, and cerebellar Purkinje cells. Virtually all of these other regions with the exception of the cerebellum also expressed pan-trk immunoreactivity in the monkey. The widespread expression of trkA throughout the central neural axis suggests that this receptor may play a role in signal transduction mechanisms linked to NGF-related substances in cholinergic basal forebrain and noncholinergic systems. These findings suggest that pharmacological use of ligands for trkA could have beneficial effects on the multiple neuronal systems that are affected in such disorders as Alzheimer's disease. (C) 1994 Wiiey-Liss, Inc.
    BibTeX:
    @article{SOBREVIELA1994,
      author = {SOBREVIELA, T and CLARY, DO and REICHARDT, LF and BRANDABUR, MM and KORDOWER, JH and MUFSON, EJ},
      title = {TRKA-IMMUNOREACTIVE PROFILES IN THE CENTRAL-NERVOUS-SYSTEM - COLOCALIZATION WITH NEURONS CONTAINING P75 NERVE GROWTH-FACTOR RECEPTOR, CHOLINE-ACETYLTRANSFERASE, AND SEROTONIN},
      journal = {JOURNAL OF COMPARATIVE NEUROLOGY},
      year = {1994},
      volume = {350},
      number = {4},
      pages = {587-611}
    }
    
    Solanto, M. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration {1998} BEHAVIOURAL BRAIN RESEARCH
    Vol. {94}({1}), pp. {127-152} 
    article  
    Abstract: The psychostimulants, D-amphetamine (D-AMP) and methylphenidate (MPH), are widely used to treat attention-deficit hyperactivity disorder (ADHD) in both children and adults. The purpose of this paper is to integrate results of basic and clinical research with stimulants in order to enhance understanding of the neuropharmacological mechanisms of therapeutic action of these drugs. Neurochemical, neurophysiological and neuroimaging studies in animals reveal that the facilitative effects of stimulants on locomotor activity, reinforcement processes, and rate-dependency are mediated by dopaminergic effects at the nucleus accumbens, whereas effects on delayed responding and working memory are mediated by noradrenergic afferents from the locus coeruleus (LC) to prefrontal cortex (PFC). Enhancing effects of the stimulants on attention and stimulus control of behavior are mediated by both dopaminergic and noradrenergic systems. In humans, stimulants appear to exert rate-dependent effects on activity levels, and primarily enhance the motor output, rather than stimulus evaluation stages of information-processing. Similarity of response of individuals with and without ADHD suggests that the stimulants do not target a specific neurobiological deficit in ADHD, but rather exert compensatory effects. Integration of evidence from pre-clinical and clinical research suggests that these effects may involve stimulation of pre-synaptic inhibitory autoreceptors, resulting in reduced activity in dopaminergic and noradrenergic pathways. The implications of these and other hypotheses for further pre-clinical and clinical research are discussed. (C) 1998 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{Solanto1998,
      author = {Solanto, MV},
      title = {Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {1998},
      volume = {94},
      number = {1},
      pages = {127-152}
    }
    
    Sonuga-Barke, E. Causal models of attention-deficit/hyperactivity disorder: From common simple deficits to multiple developmental pathways {2005} BIOLOGICAL PSYCHIATRY
    Vol. {57}({11}), pp. {1231-1238} 
    article DOI  
    Abstract: Until recently, causal models of attention-deficit/hyperactivity disorder (ADHD) have tended to focus on the role of common, simple core deficits. One such model highlights the role of executive dysfunction due to deficient inhibitory control resulting from disturbances in the frontodorsal striatal circuit and associated mesocortical dopaminergenic branches. An alternative model presents ADHD as resulting from impaired signalling of delayed rewards arising from disturbances in motivational processes, involving frontoventral striatal reward circuits and mesolimbic branches terminating in the ventral striatum, particularly the nucleus accumbens. In the present article, these models are elaborated in two ways. First, they are each placed within their developmental context by consideration of the role of person x environment correlation and interaction and individual adaptation to developmental constraint. Second, their relationship to one another is reviewed in the light of recent data suggesting that delay aversion and executive functions might each make distinctive contributions to the development of the disorder. This provides an impetus for theorethical models built around the idea of multiple neurodevelopmental pathways. The possibility of neuropathologic heterogeneity in ADHD is likely to have important implications for the clinical management of the condition, potentially impacting on both diagnostic strategies and treatment options.
    BibTeX:
    @article{Sonuga-Barke2005,
      author = {Sonuga-Barke, EJS},
      title = {Causal models of attention-deficit/hyperactivity disorder: From common simple deficits to multiple developmental pathways},
      journal = {BIOLOGICAL PSYCHIATRY},
      year = {2005},
      volume = {57},
      number = {11},
      pages = {1231-1238},
      note = {Conference on Advancing the Neuroscience of Attention-Deficit/Hyperactivity Disorder (ADHD), Boston, MA, FEB 28, 2004},
      doi = {{10.1016/j.biopsych.2004.09.008}}
    }
    
    Sonuga-Barke, E. Psychological heterogeneity in AD/HD - a dual pathway model of behaviour and cognition {2002} BEHAVIOURAL BRAIN RESEARCH
    Vol. {130}({1-2, Sp. Iss. SI}), pp. {29-36} 
    article  
    Abstract: Psychological accounts have characterised attention-deficit/hyperactivity disorder (AD/HD) as either a neuro-cognitive disorder of regulation or a motivational style. Poor inhibitory control is thought to underpin AD/HD children's dysregulation while delay aversion is a dominant characteristic of their motivational style. A recent `head to head' study of these two accounts suggest that delay aversion and poor inhibitory control are independent co-existing characteristics of AD/HD (combined type). In the present paper we build on these findings to propose a dual pathway model of AD/HD that recognises two quite distinct sub-types of the disorder. In one AD/HD is the result of the dysregulation of action and thought resulting from poor inhibitory control associated with the meso-cortical branch of the dopamine system projecting in the cortical control centres (e.g. pre-frontal cortex). In the other AD/HD is a motivational style characterised by an altered delay of reward gradient linked to the meso-limbic dopamine branch associated with the reward circuits (e.g. nucleus accumbens). The two pathways are further distinguished at the levels of symptoms, cognitive and motivation profiles and genetic and non-genetic origins. (C) 2002 Elsevier Science B.V. All rights reserved.
    BibTeX:
    @article{Sonuga-Barke2002,
      author = {Sonuga-Barke, EJS},
      title = {Psychological heterogeneity in AD/HD - a dual pathway model of behaviour and cognition},
      journal = {BEHAVIOURAL BRAIN RESEARCH},
      year = {2002},
      volume = {130},
      number = {1-2, Sp. Iss. SI},
      pages = {29-36},
      note = {Symposium on Dopamine Hypothesis of ADHD, CASTILLA LA MANCHA, SPAIN, FEB 14-25, 2000}
    }
    
    Sora, I., Hall, F., Andrews, A., Itokawa, M., Li, X., Wei, H., Wichems, C., Lesch, K., Murphy, D. & Uhl, G. Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference {2001} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {98}({9}), pp. {5300-5305} 
    article  
    Abstract: Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT, However, knockouts of neither DAT. SERT, or NET reduce cocaine reward/reinforcement. leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioural features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement. as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development.
    BibTeX:
    @article{Sora2001,
      author = {Sora, I and Hall, FS and Andrews, AM and Itokawa, M and Li, XF and Wei, HB and Wichems, C and Lesch, KP and Murphy, DL and Uhl, GR},
      title = {Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {2001},
      volume = {98},
      number = {9},
      pages = {5300-5305}
    }
    
    SORENSEN, S., KEHNE, J., FADAYEL, G., HUMPHREYS, T., KETTELER, H., SULLIVAN, C., TAYLOR, V. & SCHMIDT, C. CHARACTERIZATION OF THE 5-HT(2) RECEPTOR ANTAGONIST MDL 100907 AS A PUTATIVE ATYPICAL ANTIPSYCHOTIC - BEHAVIORAL, ELECTROPHYSIOLOGICAL AND NEUROCHEMICAL STUDIES {1993} JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    Vol. {266}({2}), pp. {684-691} 
    article  
    Abstract: Progress toward understanding the role of the 5-hydroxytryptamine (5-HT)2 receptor in the therapy for schizophrenia has been hampered by the lack of highly selective antagonists. We now report on the effects of MDL 100,907 [R(+)-alpha-(2,3-dimeth-oxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-pip eridine-methanol], a highly selective and potent 5-HT2 receptor antagonist, in behavioral, electrophysiological and neurochemical models of antipsychotic activity and extrapyramidal side-effect liability. In mice, MDL 100,907 blocked amphetamine-stimulated locomotion at doses that did not significantly affect apomorphine-stimulated climbing behavior. Neither MDL 100,907 nor clozapine reduced apomorphine-induced stereotypies or produced catalepsy in rats. MDL 100,907 blocked the slowing of ventral tegmental area (Al 0) dopaminergic neurons by amphetamine but, like clozapine, produced only small increases in the number of active substantia nigra zona compacta (A9) and Al 0 dopamine neurons after acute administration. When administered chronically, MDL 100,907 and clozapine selectively reduced the number of spontaneously active Al 0 neurons, whereas haloperidol reduced activity in both the A9 and A10 regions. Consistent with their acute effect on A9 and A10 activity, neither MDL 100,907 nor clozapine increased dopamine metabolism in the striatum or nucleus accumbens, whereas acute haloperidol accelerated dopamine turnover in both regions. The administration of the dopamine uptake blocker amfonelic acid with haloperidol produced a massive increase in DA metabolism characteristic of typical antipsychotics. In contrast, MDL 100,907 and clozapine were without effect on dopamine turnover when given in the presence of amfonelic acid. These data indicate that MDL 100,907 has a clozapine-like profile of potential antipsychotic activity with low extrapyramidal side-effect liability. The receptor selectivity of MDL 100,907 and the proposed regulation of dopaminergic function by 5-HT2 receptors support the conclusion that further clinical evaluation of selective 5-HT2 antagonists as antipsychotic agents is warranted.
    BibTeX:
    @article{SORENSEN1993,
      author = {SORENSEN, SM and KEHNE, JH and FADAYEL, GM and HUMPHREYS, TM and KETTELER, HJ and SULLIVAN, CK and TAYLOR, VL and SCHMIDT, CJ},
      title = {CHARACTERIZATION OF THE 5-HT(2) RECEPTOR ANTAGONIST MDL 100907 AS A PUTATIVE ATYPICAL ANTIPSYCHOTIC - BEHAVIORAL, ELECTROPHYSIOLOGICAL AND NEUROCHEMICAL STUDIES},
      journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
      year = {1993},
      volume = {266},
      number = {2},
      pages = {684-691}
    }
    
    SPANAGEL, R., HERZ, A. & SHIPPENBERG, T. OPPOSING TONICALLY ACTIVE ENDOGENOUS OPIOID SYSTEMS MODULATE THE MESOLIMBIC DOPAMINERGIC PATHWAY {1992} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {89}({6}), pp. {2046-2050} 
    article  
    Abstract: The mesolimbic dopaminergic system has been implicated in mediating the motivational effects of opioids and other drugs of abuse. The site of action of opioids within this system and the role of endogenous opioid peptides in modulating dopamine activity therein remain unknown. Employing the technique of in vivo microdialysis and the administration of highly selective opioid ligands, the present study demonstrates the existence of tonically active and functionally opposing-mu and kappa-opioid systems that regulate dopamine release in the nucleus accumbens, the major terminal area of A10 dopaminergic neurons. Thus, stimulation of mu-type receptors in the ventral tegmental area, the site of origin of A10 dopaminergic neurons, increases dopamine release whereas the selective blockade of this opioid receptor type results in a significant decrease in basal dopamine release. In contrast, stimulation of kappa-type receptors within the nucleus accumbens decreases dopamine release whereas their selective blockade markedly increases basal dopamine release. These data show that tonic activation of mu and kappa-receptors is required for the maintenance of basal dopamine release in the nucleus accumbens. In view of the postulated role of the mesolimbic system in the mediation of drug-induced alterations in mood and affect, such findings may have implications for the treatment of opiate dependence and affective disorders.
    BibTeX:
    @article{SPANAGEL1992,
      author = {SPANAGEL, R and HERZ, A and SHIPPENBERG, TS},
      title = {OPPOSING TONICALLY ACTIVE ENDOGENOUS OPIOID SYSTEMS MODULATE THE MESOLIMBIC DOPAMINERGIC PATHWAY},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1992},
      volume = {89},
      number = {6},
      pages = {2046-2050}
    }
    
    SPANAGEL, R., HERZ, A. & SHIPPENBERG, T. THE EFFECTS OF OPIOID-PEPTIDES ON DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS - AN INVIVO MICRODIALYSIS STUDY {1990} JOURNAL OF NEUROCHEMISTRY
    Vol. {55}({5}), pp. {1734-1740} 
    article  
    BibTeX:
    @article{SPANAGEL1990,
      author = {SPANAGEL, R and HERZ, A and SHIPPENBERG, TS},
      title = {THE EFFECTS OF OPIOID-PEPTIDES ON DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS - AN INVIVO MICRODIALYSIS STUDY},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1990},
      volume = {55},
      number = {5},
      pages = {1734-1740}
    }
    
    Spanagel, R. & Weiss, F. The dopamine hypothesis of reward: past and current status {1999} TRENDS IN NEUROSCIENCES
    Vol. {22}({11}), pp. {521-527} 
    article  
    Abstract: Mesolimbic dopaminergic neurons are thought to serve as a final common neural pathway for mediating reinforcement processes. However, several recent findings have challenged the view that mesolimbic dopamine has a crucial role in the maintenance of reinforcement processes, or the subjective rewarding actions of natural rewards and drugs of abuse, Instead, there is growing evidence that dopamine is involved in the formation of associations between salient contextual stimuli and internal rewarding or aversive events,This evidence suggests that dopaminergic-neuron activation aids the organism in learning to recognize stimuli associated with such events. Thus, mesolimbic dopaminergic neurons have an important function in the acquisition of behavior reinforced by natural reward and drug stimuli, Furthermore, long-lasting neuroadaptive changes in mesolimbic dopamine-mediated transmission that develop during chronic drug use might contribute to compulsive drug-seeking behavior and relapse.
    BibTeX:
    @article{Spanagel1999,
      author = {Spanagel, R and Weiss, F},
      title = {The dopamine hypothesis of reward: past and current status},
      journal = {TRENDS IN NEUROSCIENCES},
      year = {1999},
      volume = {22},
      number = {11},
      pages = {521-527}
    }
    
    Spanagel, R. & Zieglgansberger, W. Anti-craving compounds for ethanol: New pharmacological tools to study addictive processes {1997} TRENDS IN PHARMACOLOGICAL SCIENCES
    Vol. {18}({2}), pp. {54-59} 
    article  
    Abstract: Anti-craving compounds have recently been registered for relapse prophylaxis in weaned alcoholics in various European countries (acamprosate), and in the United States (naltrexone). Acamprosate, the Ca2+-salt of N-acetyl-homotaurinate, interacts with NMDB receptor-mediated glutamatergic neurotransmission in various brain regions and reduces Ca2+ fluxes through voltage-operated channels. The opioid receptor antagonist naltrexone most likely interferes with alcohol-induced reinforcement via the block of opioid receptors. In this article Rainer Spanagel and Walter Zieglgansberger discuss the pivotal role of incremental neuroadaptation to alcohol and alcohol-associated stimuli for craving, and the possible mechanisms of action underlying the anti-craving properties of acamprosate and naltrexone.
    BibTeX:
    @article{Spanagel1997,
      author = {Spanagel, R and Zieglgansberger, W},
      title = {Anti-craving compounds for ethanol: New pharmacological tools to study addictive processes},
      journal = {TRENDS IN PHARMACOLOGICAL SCIENCES},
      year = {1997},
      volume = {18},
      number = {2},
      pages = {54-59}
    }
    
    Spear, L. The adolescent brain and age-related behavioral manifestations {2000} NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
    Vol. {24}({4}), pp. {417-463} 
    article  
    Abstract: To successfully negotiate the developmental transition between youth and adulthood, adolescents must maneuver this often stressful period while acquiring skills necessary for independence. Certain behavioral features, including age-related increases in social behavior and risk-taking/novelty-seeking, are common among adolescents of diverse mammalian species and may aid in this process. Reduced positive incentive values from stimuli may lead adolescents to pursue new appetitive reinforcers through drug use and other risk-taking behaviors, with their relative insensitivity to drugs supporting comparatively greater per occasion use. Pubertal increases in gonadal hormones are a hallmark of adolescence, although there is little evidence for a simple association of these hormones with behavioral change during adolescence. Prominent developmental transformations are seen in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems. Developmental changes in these stressor-sensitive regions, which are critical for attributing incentive salience to drugs and other stimuli, likely contribute to the unique characteristics of adolescence. (C) 2000 Elsevier Science Ltd. All rights reserved.
    BibTeX:
    @article{Spear2000,
      author = {Spear, LP},
      title = {The adolescent brain and age-related behavioral manifestations},
      journal = {NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS},
      year = {2000},
      volume = {24},
      number = {4},
      pages = {417-463}
    }
    
    Stein, E., Pankiewicz, J., Harsch, H., Cho, J., Fuller, S., Hoffmann, R., Hawkins, M., Rao, S., Bandettini, P. & Bloom, A. Nicotine-induced limbic cortical activation in the human brain: A functional MRI study {1998} AMERICAN JOURNAL OF PSYCHIATRY
    Vol. {155}({8}), pp. {1009-1015} 
    article  
    Abstract: Nicotine is a highly addictive substance, and cigarette smoking is a major cause of premature death among humans. Little is known about the neuropharmacology and sites of action of nicotine in the human brain. Such knowledge might help in the development of new behavioral and pharmacological therapies to aid in treating nicotine dependence and to improve smoking cessation success rates. Method: Functional magnetic resonance imaging, a real-time imaging technique, was used to determine the acute CNS effects of intravenous nicotine in 16 active cigarette smokers. An injection of saline followed by injections of three doses of nicotine (0.75, 1.50, and 2.25 mg/70 kg of weight) were each administered intravenously over 1-minute periods in an ascending, cumulative-dosing paradigm while whole brain gradient-echo, echo-planar images were acquired every 6 seconds during consecutive 20-minute trials. Results: Nicotine induced a dose-dependent increase in several behavioral parameters, including feelings of ``rush'' and ``high'' and drug liking. Nicotine also induced a dose-dependent increase in neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes. Activation in these structures is consistent with nicotine's behavior-arousing and behavior-reinforcing properties in humans. Conclusions: The identified brain regions have been previously shown to participate in the reinforcing, mood-elevating, and cognitive properties of other abused drugs such as cocaine, amphetamine, and opiates, suggesting that nicotine acts similarly in the human brain to produce its reinforcing and dependence properties.
    BibTeX:
    @article{Stein1998,
      author = {Stein, EA and Pankiewicz, J and Harsch, HH and Cho, JK and Fuller, SA and Hoffmann, RG and Hawkins, M and Rao, SM and Bandettini, PA and Bloom, AS},
      title = {Nicotine-induced limbic cortical activation in the human brain: A functional MRI study},
      journal = {AMERICAN JOURNAL OF PSYCHIATRY},
      year = {1998},
      volume = {155},
      number = {8},
      pages = {1009-1015},
      note = {57th Annual Scientific Meeting of the College-on-Problems-of-Drug-Dependence, SCOTTSDALE, ARIZONA, JUN 11-16, 1995}
    }
    
    Steiner, H. & Gerfen, C. Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior {1998} EXPERIMENTAL BRAIN RESEARCH
    Vol. {123}({1-2}), pp. {60-76} 
    article  
    Abstract: Projection neurons in the striatum give rise to two output systems, the ``direct'' and ``indirect'' pathways, which antagonistically regulate basal ganglia output. While all striatal projection neurons utilize GABA as their principal neurotransmitter, they express different opioid peptide co-transmitters and also different dopamine receptor subtypes. Neurons of the direct pathway express the peptide dynorphin and the D1 dopamine receptor, whereas indirect pathway neurons express the peptide enkephalin and the D2 receptor. In the present review, we summarize our findings on the function of dynorphin and enkephalin in these striatal output pathways. In these studies, we used D1- or D2-receptor-mediated induction of immediate-early genes as a cellular response in direct or indirect projection neurons, respectively, to investigate the role of these opioid peptides. Our results suggest that the specific function of dynorphin and enkephalin is to dampen excessive activation of these neurons by dopamine and other neurotransmitters. Levels of these opioid peptides are elevated by repeated, excessive activation of these pathways, which appears to be an adaptive or compensatory response. Behavioral consequences of increased opioid peptide function in striatal output pathways may include behavioral sensitization (dynorphin) and recovery of motor function (enkephalin).
    BibTeX:
    @article{Steiner1998,
      author = {Steiner, H and Gerfen, CR},
      title = {Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior},
      journal = {EXPERIMENTAL BRAIN RESEARCH},
      year = {1998},
      volume = {123},
      number = {1-2},
      pages = {60-76},
      note = {29th Annual Meeting of the European-Brain-and-Behaviour-Society, TUTZING, GERMANY, SEP 15-18, 1997}
    }
    
    STEINER, H. & GERFEN, C. COCAINE-INDUCED C-FOS MESSENGER-RNA IS INVERSELY RELATED TO DYNORPHIN EXPRESSION IN STRIATUM {1993} JOURNAL OF NEUROSCIENCE
    Vol. {13}({12}), pp. {5066-5081} 
    article  
    Abstract: The effects of the indirect dopamine receptor agonist cocaine in the striatum on levels of mRNAs of the immediate-early gene c-fos and the neuropeptides dynorphin, substance P, and enkephalin were analyzed with quantitative in situ hybridization histochemistry. Both single (acute) and repeated (twice a day for 4 d) systemic injections of cocaine (3.75-30 mg/kg) to rats resulted in dose-dependent, regionally specific elevations of mRNA expression in striatal neurons. A single drug treatment elevated c-fos mRNA expression, whereas repeated treatments resulted in little c-fos expression but elevated dynorphin mRNA levels. Both the regional and temporal patterns of gene expression revealed an inverse relationship between dynorphin and c-fos expression. This relationship was examined in a time course experiment in which cocaine (30 mg/kg) was administered for 1, 2, 3 or 4 d. Basal levels of dynorphin expression were relatively high in the ventral striatum, including the nucleus accumbens, a ventrolateral region, and an area along the medial bank of the striatum. A single injection of cocaine induced c-fos mRNA in striatal areas with low basal expression of dynorphin. Thus, c-fos mRNA induction was highest in the dorsal central striatum, where basal dynorphin mRNA levels were lowest. In this region, dynorphin mRNA expression increased on subsequent treatment days parallel to diminished c-fos mRNA induction. Changes in substance P mRNA levels appeared to match directly both the temporal and regional patterns of c-fos induction. Enkephalin mRNA expression was altered, but only slightly, by these cocaine treatments. Statistical analysis of the regional patterns of basal and altered mRNA levels shows a unique inverse relationship between basal dynorphin expression and c- fos induction by cocaine. Further evidence of this relationship is provided by the dose-dependent blockade of cocaine-induced c-fos expression by spiradoline, a dynorphin agonist. Together, these results suggest that the restricted regional pattern of cocaine-induced c-fos expression is related, in part, to the basal level of dynorphin expression, and that cocaine treatment elevates dynorphin expression in striatal regions with a strong c-fos response, thereby limiting subsequent c-fos induction by cocaine. These findings lead to the hypothesis that dynorphin acts to regulate the responsiveness of striatal neurons to dopamine stimulation.
    BibTeX:
    @article{STEINER1993,
      author = {STEINER, H and GERFEN, CR},
      title = {COCAINE-INDUCED C-FOS MESSENGER-RNA IS INVERSELY RELATED TO DYNORPHIN EXPRESSION IN STRIATUM},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1993},
      volume = {13},
      number = {12},
      pages = {5066-5081}
    }
    
    STEWART, J. & BADIANI, A. TOLERANCE AND SENSITIZATION TO THE BEHAVIORAL-EFFECTS OF DRUGS {1993} BEHAVIOURAL PHARMACOLOGY
    Vol. {4}({4}), pp. {289-312} 
    article  
    Abstract: Tolerance and sensitization are relatively simple manifestations of learning and memory that refer to decreases and increases in the strength of a response to a stimulus induced by past experiences with the same or related stimuli. In the context of the study of drugs, tolerance refers to the decreased effectiveness of a given drug with repeated administration; sensitization to the increased effectiveness with repeated administration. Tolerance usually involves active adjustments or adaptation to the drug-induced disturbances of function, either within cells or within a neural system. In situations involving inter-neuronal events, these processes of adjustment may take the form of learned modifications that can be re-evoked on future occasions by events that co-occurred at the time of the original modifications. Sensitization, defined as the enhancement of a directly elicited drug effect, though adaptive, appears to represent facilitation within a system, making the effect easier to elicit on future occasions. Like tolerance, sensitization of a drug effect can become linked to the events that co-occurred when the effect was originally elicited, making it possible for sensitization to come under selective event control. This paper is concerned with factors that affect whether tolerance and/or sensitization to the various effects of drugs will develop and be expressed, and with the variety and levels of mechanisms responsible for tolerance and sensitization under different conditions of exposure.
    BibTeX:
    @article{STEWART1993,
      author = {STEWART, J and BADIANI, A},
      title = {TOLERANCE AND SENSITIZATION TO THE BEHAVIORAL-EFFECTS OF DRUGS},
      journal = {BEHAVIOURAL PHARMACOLOGY},
      year = {1993},
      volume = {4},
      number = {4},
      pages = {289-312}
    }
    
    STINUS, L., LEMOAL, M. & KOOB, G. NUCLEUS-ACCUMBENS AND AMYGDALA ARE POSSIBLE SUBSTRATES FOR THE AVERSIVE STIMULUS EFFECTS OF OPIATE WITHDRAWAL {1990} NEUROSCIENCE
    Vol. {37}({3}), pp. {767-773} 
    article  
    BibTeX:
    @article{STINUS1990,
      author = {STINUS, L and LEMOAL, M and KOOB, GF},
      title = {NUCLEUS-ACCUMBENS AND AMYGDALA ARE POSSIBLE SUBSTRATES FOR THE AVERSIVE STIMULUS EFFECTS OF OPIATE WITHDRAWAL},
      journal = {NEUROSCIENCE},
      year = {1990},
      volume = {37},
      number = {3},
      pages = {767-773}
    }
    
    STOLERMAN, I. & JARVIS, M. THE SCIENTIFIC CASE THAT NICOTINE IS ADDICTIVE {1995} PSYCHOPHARMACOLOGY
    Vol. {117}({1}), pp. {2-10} 
    article  
    Abstract: Despite the wide-ranging and authoritative 1988 review by the US Surgeon General, views questioning the addictiveness of nicotine contine to be expressed in some quarters. This lack of complete consensus is not unexpected, since no universally agreed scientific definition of addiction exists. In this paper we briefly consider a number of lines of evidence from both the human and animal literature bearing on the addictiveness of nicotine. Patterns of use by smokers and the remarkable intractability of the smoking habit point to compulsive use as the norm. Studies in both animal and human subjects have shown that nicotine can function as reinforcer, albeit under a more limited range of conditions than with some other drugs of abuse. In drug discrimination paradigms there is some cross-generalisation between nicotine on the one hand, and amphetamine and cocaine on the other. A well-defined nicotine withdrawal syndrome has been delineated which is alleviated by nicotine replacement. Nicotine replacement also enhances outcomes in smoking cessation, roughly doubling success rates. In total, the evidence clearly identifies nicotine as a powerful drug of addiction, comparable to heroin, cocaine and alcohol.
    BibTeX:
    @article{STOLERMAN1995,
      author = {STOLERMAN, IP and JARVIS, MJ},
      title = {THE SCIENTIFIC CASE THAT NICOTINE IS ADDICTIVE},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1995},
      volume = {117},
      number = {1},
      pages = {2-10}
    }
    
    Stratford, T. & Kelley, A. GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior {1997} JOURNAL OF NEUROSCIENCE
    Vol. {17}({11}), pp. {4434-4440} 
    article  
    Abstract: We have demonstrated previously that injections of 6,7-dinitroquinoxaline-2,3-dione into the nucleus accumbens shell (AcbSh) elicits pronounced feeding in satiated rats. This glutamate antagonist blocks AMPA and kainate receptors and most likely increases food intake by disrupting a tonic excitatory input to the AcbSh, thus decreasing the firing rate of a population of local neurons. Because the application of GABA agonists also decreases neuronal activity, we hypothesized that administration of GABA agonists into the AcbSh would stimulate feeding in satiated rats. We found that acute inhibition of cells in the AcbSh via administration of the GABA(A) receptor agonist muscimol or the GABA(B) receptor agonist baclofen elicited intense, dose-related feeding without altering water intake. Muscimol-induced feeding was blocked by coadministration of the selective GABA(A) receptor blocker bicuculline, but not by the GABA(B) receptor blocker saclofen. Conversely, baclofen-induced feeding was blocked by coadministration of saclofen, but was not affected by bicuculline. Furthermore, we found that increasing local levels of GABA by administration of a selective GABA-transaminase inhibitor, gamma-vinyl-GABA, elicited robust feeding in satiated rats, suggesting a physiological role for endogenous AcbSh GABA in the control of feeding. A mapping study showed that although some feeding can be elicited by muscimol injections near the lateral ventricles, the ventromedial AcbSh is the most sensitive site for eliciting feeding. These findings demonstrate that manipulation of GABA-sensitive cells in the AcbSh can have a pronounced, but specific, effect on feeding behavior in rats. They also constitute the initial description of a novel and potentially important component of the central mechanisms controlling food intake.
    BibTeX:
    @article{Stratford1997,
      author = {Stratford, TR and Kelley, AE},
      title = {GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1997},
      volume = {17},
      number = {11},
      pages = {4434-4440}
    }
    
    SUAUDCHAGNY, M., CHERGUI, K., CHOUVET, G. & GONON, F. RELATIONSHIP BETWEEN DOPAMINE RELEASE IN THE RAT NUCLEUS-ACCUMBENS AND THE DISCHARGE ACTIVITY OF DOPAMINERGIC-NEURONS DURING LOCAL INVIVO APPLICATION OF AMINO-ACIDS IN THE VENTRAL TEGMENTAL AREA {1992} NEUROSCIENCE
    Vol. {49}({1}), pp. {63-72} 
    article  
    Abstract: Amino acids were pressure-ejected in the ventral tegmental area of rats which were anesthetized with chloral hydrate and treated with pargyline. The extracellular dopamine concentration was recorded from the nucleus accumbens with an electrochemically treated carbon fiber electrode combined either with differential normal pulse voltammetry or with differential pulse amperometry. In distinct rats the discharge activity of single dopaminergic neurons was monitored in the ventral tegmental area while amino acids were pressure-injected at a distance of 200-300-mu-m from the recorded cell. GABA (24 and 50nl, 1 M) induced a complete and reversible inhibition of the firing rate lasting for 3-6min and a decrease in the basal extracellular dopamine level (-54% and -66 respectively). Glutamate (32nl, 10mM), N-methyl-D-aspartate and quisqualate (100-mu-M) stimulated the firing rate and enhanced the dopamine extracellular concentration up to 10-times the basal one (18 nM). These increases subsided within 1-5 min. Their amplitude depended on the ejected volume (from 16 to 65 n]). At the time-resolution of the method (some seconds) all these variations in the dopamine release appeared closely time-correlated with those of the firing rate. When the mean discharge rate is considered, N-methyl-D-aspartate was as potent as quisqualate but the former promoted burst firing while the latter induced a sustained activity. As regards dopamine release, N-methyl-D-aspartate was twice as potent as quisqualate. This further shows that dopaminergic terminals convert physiological impulse flow into dopamine release as a high pass filter which favors bursts of action potentials.
    BibTeX:
    @article{SUAUDCHAGNY1992,
      author = {SUAUDCHAGNY, MF and CHERGUI, K and CHOUVET, G and GONON, F},
      title = {RELATIONSHIP BETWEEN DOPAMINE RELEASE IN THE RAT NUCLEUS-ACCUMBENS AND THE DISCHARGE ACTIVITY OF DOPAMINERGIC-NEURONS DURING LOCAL INVIVO APPLICATION OF AMINO-ACIDS IN THE VENTRAL TEGMENTAL AREA},
      journal = {NEUROSCIENCE},
      year = {1992},
      volume = {49},
      number = {1},
      pages = {63-72}
    }
    
    SULZER, D. & RAYPORT, S. AMPHETAMINE AND OTHER PSYCHOSTIMULANTS REDUCE PH GRADIENTS IN MIDBRAIN DOPAMINERGIC-NEURONS AND CHROMAFFIN GRANULES - A MECHANISM OF ACTION {1990} NEURON
    Vol. {5}({6}), pp. {797-808} 
    article  
    Abstract: Rewarding properties of psychostimulants result from reduced uptake and/or increased release of dopamine at mesolimbic synapses. As exemplified by cocaine, many psychostimulants act by binding to the dopamine uptake transporter. However, this does not explain the action of other psychostimulants, including amphetamine. As most psychostimulants are weak bases and dopamine uptake into synaptic vesicles uses an interior-acidic pH gradient, we examined the possibility that psychostimulants might inhibit acidification. Pharmacologically relevant concentrations of amphetamine as well as cocaine and phencyclidine rapidly reduced pH gradients in cultured midbrain dopaminergic neurons. To examine direct effects on vesicles, we used chromaffin granules. The three psychostimulants, as well as fenfluramine, imipramine, and tyramine, reduced the pH gradient, resulting in reduced uptake and increased release of neurotransmitter. Inhibition of acidification by psychoactive amines contributes to their pharmacology and may provide a principal molecular mechanism of action of amphetamine.
    BibTeX:
    @article{SULZER1990,
      author = {SULZER, D and RAYPORT, S},
      title = {AMPHETAMINE AND OTHER PSYCHOSTIMULANTS REDUCE PH GRADIENTS IN MIDBRAIN DOPAMINERGIC-NEURONS AND CHROMAFFIN GRANULES - A MECHANISM OF ACTION},
      journal = {NEURON},
      year = {1990},
      volume = {5},
      number = {6},
      pages = {797-808}
    }
    
    SURMEIER, D., EBERWINE, J., WILSON, C., CAO, Y., STEFANI, A. & KITAI, S. DOPAMINE RECEPTOR SUBTYPES COLOCALIZE IN RAT STRIATONIGRAL NEURONS {1992} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {89}({21}), pp. {10178-10182} 
    article  
    Abstract: Dopaminergic neurons of the substantia nigra provide one of the major neuromodulatory inputs to the neostriatum. Recent in situ hybridization experiments have suggested that postsynaptic dopamine receptors are segregated in striatonigral and striatopallidal neurons. We have tested this hypothesis in acutely isolated, retrogradely labeled striatonigral neurons by examining the neuromodulatory effects of selective dopaminergic agonists on Na currents and by probing single-cell antisense RNA populations with dopamine receptor cDNAs. In most of the neurons examined (20/31), the application of the D1 dopamine receptor agonist SKF 38393 reduced evoked whole-cell Na+ current. The D2 agonists quinpirole and bromocriptine had mixed effects; in most neurons (23/42), whole-cell Na+ currents were reduced, but in others (8/42), currents were increased. In cell-attached patch recordings, bath application of SKF 38393 decreased currents as in whole-cell recordings, whereas quinpirole consistently (6/10) enhanced currents-suggesting that D2-like receptors could act through membrane delimited and non-delimited pathways. Changes in evoked current were produced by modulation of peak conductance and modest shifts in the voltage dependence of steady-state inactivation. Antisense RNA probes of dopamine receptor cDNA Southern blots consistently (515) revealed the presence of D1, D2, and D3 receptor mRNA in single striatonigral neurons. These findings argue that, contrary to a strict receptor segregation hypothesis, many striatonigral neurons colocalize functional D1, D2, and D3 receptors.
    BibTeX:
    @article{SURMEIER1992,
      author = {SURMEIER, DJ and EBERWINE, J and WILSON, CJ and CAO, Y and STEFANI, A and KITAI, ST},
      title = {DOPAMINE RECEPTOR SUBTYPES COLOCALIZE IN RAT STRIATONIGRAL NEURONS},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1992},
      volume = {89},
      number = {21},
      pages = {10178-10182}
    }
    
    Surmeier, D., Song, W. & Yan, Z. Coordinated expression of dopamine receptors in neostriatal medium spiny neurons {1996} JOURNAL OF NEUROSCIENCE
    Vol. {16}({20}), pp. {6579-6591} 
    article  
    Abstract: In recent years, the distribution of dopamine receptor subtypes among the principal neurons of the neostriatum has been the subject of debate. Conventional anatomical and physiological approaches have yielded starkly different estimates of the extent to which D-1 and D-2 class dopamine receptors are colocalized. One plausible explanation for the discrepancy is that some dopamine receptors are present in physiologically significant numbers, but the mRNA for these receptors is not detectable with conventional techniques. To test this hypothesis, we examined the expression of DA receptors in individual neostriatal neurons by patch-clamp and RT-PCR techniques. Because of the strong correlation between peptide expression and projection site, medium spiny neurons were divided into three groups on the basis of expression of mRNA for enkephalin (ENK) and substance P (SP). Neurons expressing detectable levels of SP but not ENK had abundant mRNA for the D-1a receptor. A subset of these cells (similar to 50 coexpressed D-3 or D-4 receptor mRNA. Neurons expressing detectable levels of ENK but not SP had abundant mRNA for D-2 receptor isoforms (short and long). A subset (10-25 of these neurons coexpressed D-1a or D-1b mRNAs. Neurons coexpressing ENK and SP mRNAs consistently coexpressed D-1a and D-2 mRNAs in relatively high abundance. Functional analysis of neurons expressing lower abundance mRNAs revealed clear physiological consequences that could be attributed to these receptors. These results suggest that, although colocalization of D-1a and D-2 receptors is limited, functional D-1 and D-2 class receptors are colocalized in nearly one-half of all medium spiny projection neurons.
    BibTeX:
    @article{Surmeier1996,
      author = {Surmeier, DJ and Song, WJ and Yan, Z},
      title = {Coordinated expression of dopamine receptors in neostriatal medium spiny neurons},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1996},
      volume = {16},
      number = {20},
      pages = {6579-6591}
    }
    
    SWANSON, L. & COWAN, W. CONNECTIONS AND DEVELOPMENT OF NUCLEUS ACCUMBENS {1975} BRAIN RESEARCH
    Vol. {92}({2}), pp. {324-330} 
    article  
    BibTeX:
    @article{SWANSON1975,
      author = {SWANSON, LW and COWAN, WM},
      title = {CONNECTIONS AND DEVELOPMENT OF NUCLEUS ACCUMBENS},
      journal = {BRAIN RESEARCH},
      year = {1975},
      volume = {92},
      number = {2},
      pages = {324-330}
    }
    
    SWERDLOW, N., BRAFF, D., TAAID, N. & GEYER, M. ASSESSING THE VALIDITY OF AN ANIMAL-MODEL OF DEFICIENT SENSORIMOTOR GATING IN SCHIZOPHRENIC-PATIENTS {1994} ARCHIVES OF GENERAL PSYCHIATRY
    Vol. {51}({2}), pp. {139-154} 
    article  
    Abstract: Psychiatric researchers need specific animal models to better understand the neurobiology of schizophrenia. Prepulse inhibition (PPI), the reduction in startle produced by a prepulse stimulus, is diminished in schizophrenic patients. Theoretically, deficient PPI in schizophrenic patients reflects a loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In rats, PPI is disrupted by systemic administration of dopamine agonists or by manipulations of neural circuitry linking the limbic cortex, striatum, pallidum, and pontine reticular formation. This loss of PPI in rats may be a useful model for studying the neurobiology of impaired sensorimotor gating in schizophrenic patients. We assessed the face, predictive, and construct validity of this animal model. Face validity was supported: stimulus manipulations produced parallel changes in PPI in humans and rats, and the dopamine agonist apomorphine disrupted PPI in rats, mimicking PPI deficits in schizophrenics. Predictive validity was supported: the ability of antipsychotics to restore PPI in apomorphine-treated rats correlated with clinical antipsychotic potency (r(s)=.991) and D-2-receptor affinity (r(s)=.893). Antipsychotics that restore PPI in apomorphine-treated rats include `'typical'' antipsychotics and the `'atypical'' antipsychotic clozapine. Construct validity was supported: PPI was disrupted in rats when dopamine was infused into the nucleus accumbens; this effect was blocked by haloperidol. The loss of PPI in dopamine-activated rats maybe a valid animal model of sensorimotor gating deficits in schizophrenic patients. This model may help us understand the neurobiology of cognitive deficits in schizophrenic patients.
    BibTeX:
    @article{SWERDLOW1994,
      author = {SWERDLOW, NR and BRAFF, DL and TAAID, N and GEYER, MA},
      title = {ASSESSING THE VALIDITY OF AN ANIMAL-MODEL OF DEFICIENT SENSORIMOTOR GATING IN SCHIZOPHRENIC-PATIENTS},
      journal = {ARCHIVES OF GENERAL PSYCHIATRY},
      year = {1994},
      volume = {51},
      number = {2},
      pages = {139-154}
    }
    
    Swerdlow, N. & Geyer, M. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia {1998} SCHIZOPHRENIA BULLETIN
    Vol. {24}({2}), pp. {285-301} 
    article  
    Abstract: Certain animal models can greatly enhance our understanding of the neurobiology of schizophrenia and can be used to predict the antipsychotic activity of compounds. Prepulse inhibition (PPI), the reduction in startle produced by a prepulse stimulus, is diminished in schizophrenia patients. Theoretically, deficient PPI in schizophrenia patients is a measure of the loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In rats, PPI is disrupted by systemic administration of dopamine agonists, serotonin agonists, or glutamate antagonists and by a variety of surgical or pharmacological manipulations of neural circuitry linking the limbic cortex, striatum, pallidum, and pontine reticular formation. This article describes several different ways the loss of PPI in rats can be used as a model for studying the pathophysiology and neurobiology of impaired sensorimotor gating in schizophrenia patients and for predicting antipsychotic activity in novel compounds. First, new experimental strategies may be used to distinguish behavioral profiles of ``typical'' versus ``atypical'' antipsychotics. Second, this paradigm can be used to study the effects of early developmental insults-including neonatal lesions and isolated rearing-on the adult emergence of deficient sensorimotor gating. Third, using different animal strains and species, as well as gene ``knockout'' strategies, greatly increases our ability to understand specific genetic or receptor contributions to the regulation of deficient PPI. Each of these uses of the PPI paradigm is enhanced by studies of the basic brain substrates that regulate PPI in rats and by the increasingly sophisticated assessments of PPI and related measures in schizophrenia spectrum patients.
    BibTeX:
    @article{Swerdlow1998,
      author = {Swerdlow, NR and Geyer, MA},
      title = {Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia},
      journal = {SCHIZOPHRENIA BULLETIN},
      year = {1998},
      volume = {24},
      number = {2},
      pages = {285-301}
    }
    
    Swerdlow, N., Geyer, M. & Braff, D. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges {2001} PSYCHOPHARMACOLOGY
    Vol. {156}({2-3}), pp. {194-215} 
    article  
    Abstract: Rationale: Sensorimotor gating of the startle reflex can be assessed across species, using similar stimuli to elicit similar responses. Prepulse inhibition (PPI), a measure of sensorimotor gating, is reduced in patients with some neuropsychiatric disorders, and in rats after manipulations of limbic cortex. striatum, pallidum or pontine tegmentum (''CSPP'' circuitry). Objective: To review the current knowledge of the neural circuit regulation of PPI in rats, and to anticipate the future challenges facing this line of inquiry. Methods: The published literature was reviewed and critically evaluated. Results: Limbic CSPP circuitry has been studied in rats to reveal the neurochemical and neuroanatomical substrates regulating PPI at a high level of resolution. In translational cross-species research, this detailed circuit information is used as a ``blueprint'' to identify substrates that may lead to PPI deficits in psychiatrically disordered humans. Some human disorders with identifiable, localized lesions in CSPP circuitry may provide direct validation for the contribution of CSPP circuitry to this cross-species model. The rapid collection of experimental data supporting this cross-species PPI circuit ``blueprint'' has supported continuing advances in the development of theoretical models for understanding how this circuitry normally functions to regulate PPI. Such models are needed for building a conceptual framework for understanding the role of this circuitry in the regulation of sensorimotor gating in normal humans, and in the relative loss of sensorimotor gating, and the resulting clinical consequences, in individuals with particular neuropsychiatric disorders. Conclusions: Our understanding of the neural regulation of PPI has increased tremendously over the past 15 years. Progress has come in ``broad strokes'', and a number of important details and complex questions remain to be addressed. It is anticipated that this is a ``work in progress'', and that the precise models for the neural regulation of PPI will evolve substantially in the coming years.
    BibTeX:
    @article{Swerdlow2001,
      author = {Swerdlow, NR and Geyer, MA and Braff, DL},
      title = {Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges},
      journal = {PSYCHOPHARMACOLOGY},
      year = {2001},
      volume = {156},
      number = {2-3},
      pages = {194-215}
    }
    
    SWERDLOW, N., PAULSEN, J., BRAFF, D., BUTTERS, N., GEYER, M. & SWENSON, M. IMPAIRED PREPULSE INHIBITION OF ACOUSTIC AND TACTILE STARTLE RESPONSE IN PATIENTS WITH HUNTINGTONS-DISEASE {1995} JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
    Vol. {58}({2}), pp. {192-200} 
    article  
    Abstract: The corpus striatum serves a critical function in inhibiting involuntary, intrusive movements. Striatal degeneration in Huntington's disease results in a loss of motor inhibition, manifested by abnormal involuntary choreiform movements. Sensorimotor inhibition, or `'gating'', can be measured in humans using the startle reflex: the startle reflex is normally inhibited when the startling stimulus is preceded 30-500 ms earlier by a weak prepulse. In the present study, prepulse inhibition (PPI) was measured in patients with Huntington's disease to quantify and characterise sensorimotor gating. Compared with age matched controls, patients with Huntington's disease exhibit less PPI. Startle gating deficits are evident in patients with Huntington's disease when startle is elicited by either acoustic or tactile stimuli. Even with stimuli that elicit maximal PPI in normal subjects, patients with Huntington's disease exhibit little or no PPI, and their pattern of startle gating does not show the normal modulatory effects usually elicited by changing the prepulse interval or intensity. Startle amplitude and habituation and latency facilitation are largely intact in these patients, although reflex latency is significantly slowed. In patients Huntingon's disease, startle slowing correlates with cognitive impairment measured by the dementia rating scale, and with the performance disruptive effects of interference measured by the Stroop test. These findings document a profound disruption of sensorimotor gating in patients with Huntingon's disease and are consistent with preclinical findings that identify the striatum and striatopallidal GABAergic efferent circuitry as critical substrates for sensorimotor gating of the startle reflex.
    BibTeX:
    @article{SWERDLOW1995,
      author = {SWERDLOW, NR and PAULSEN, J and BRAFF, DL and BUTTERS, N and GEYER, MA and SWENSON, MR},
      title = {IMPAIRED PREPULSE INHIBITION OF ACOUSTIC AND TACTILE STARTLE RESPONSE IN PATIENTS WITH HUNTINGTONS-DISEASE},
      journal = {JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY},
      year = {1995},
      volume = {58},
      number = {2},
      pages = {192-200}
    }
    
    TABER, M. & FIBIGER, H. ELECTRICAL-STIMULATION OF THE PREFRONTAL CORTEX INCREASES DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS OF THE RAT - MODULATION BY METABOTROPIC GLUTAMATE RECEPTORS {1995} JOURNAL OF NEUROSCIENCE
    Vol. {15}({5, Part 2}), pp. {3896-3904} 
    article  
    Abstract: In vivo microdialysis was used to assess the effects of electrical stimulation of the prefrontal cortex (PFC) on dopamine (DA) release in the nucleus accumbens (NAG) of awake, unrestrained rats. The PFC was stimulated bilaterally for 20 min at parameters previously shown to support intracranial self-stimulation in this structure, Stimulation at 50 mu A evoked a 38% increase in DA release while 100 mu A produced a 69% increase, Thus, phasic activation of the PFC increases DA release in the NAG. Additional experiments were performed to establish whether glutamate receptors in the NAC mediated these effects, The noncompetitive NMDA antagonist dizocilpine maleate (MK-801) and the broad spectrum competitive antagonist kynurenic acid were each applied locally to the NAC via reverse dialysis alone or in combination with electrical stimulation of the PFC (100 mu A). Both MK-801 (10 mu M) and kynurenic acid (5 mM) increased DA release when administered alone, When a `'subthreshold'' concentration (i.e., the highest concentration employed that did not itself increase DA release) of either compound was administered together with PFC stimulation, neither kynurenic acid (1 mM) nor MK-801 (1 mu M) attenuated the effect of stimulation on DA release, thereby indicating that this effect is not mediated by ionotropic glutamate receptors located within the NAC. To examine the possible role of metabotropic glutamate receptors in regulating DA release, the metabotropic glutamate agonist trans(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) was employed, When applied locally to the NAG, ACPD had a dose-dependent effect on DA release with a high concentration (1 mM) causing an increase and a lower concentration (100 mu M) causing a small decrease. The latter concentration blocked PFC stimulation (100 mu A)-induced increases in DA release in the NAG. To determine whether this finding reflected a general inhibitory effect of ACPD on stimulated DA release, ACPD was also applied during electrical stimulation (20 mu A) of the ventral tegmental area, the origin of the mesoaccumbens DA projection. Again, ACPD (100 mu M) blocked the stimulation-induced increase in DA release, These findings demonstrate that (1) phasic activation of the PFC increases DA release in the NAG, (2) this effect is not mediated by ionotropic glutamate receptors in the NAG, and (3) local metabotropic receptors serve to inhibit stimulation-induced increases in transmitter release from mesoaccumbens DA terminals. These results provide further evidence for functional interactions between metabotropic glutamate receptors and DA in the limbic striatum.
    BibTeX:
    @article{TABER1995,
      author = {TABER, MT and FIBIGER, HC},
      title = {ELECTRICAL-STIMULATION OF THE PREFRONTAL CORTEX INCREASES DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS OF THE RAT - MODULATION BY METABOTROPIC GLUTAMATE RECEPTORS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1995},
      volume = {15},
      number = {5, Part 2},
      pages = {3896-3904}
    }
    
    Tanaka, S., Doya, K., Okada, G., Ueda, K., Okamoto, Y. & Yamawaki, S. Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops {2004} NATURE NEUROSCIENCE
    Vol. {7}({8}), pp. {887-893} 
    article DOI  
    Abstract: Evaluation of both immediate and future outcomes of one's actions is a critical requirement for intelligent behavior. Using functional magnetic resonance imaging (fMRI), we investigated brain mechanisms for reward prediction at different time scales in a Markov decision task. When human subjects learned actions on the basis of immediate rewards, significant activity was seen in the lateral orbitofrontal cortex and the striatum. When subjects learned to act in order to obtain large future rewards while incurring small immediate losses, the dorsolateral prefrontal cortex, inferior parietal cortex, dorsal raphe nucleus and cerebellum were also activated. Computational model-based regression analysis using the predicted future rewards and prediction errors estimated from subjects' performance data revealed graded maps of time scale within the insula and the striatum: ventroanterior regions were involved in predicting immediate rewards and dorsoposterior regions were involved in predicting future rewards. These results suggest differential involvement of the cortico-basal ganglia loops in reward prediction at different time scales.
    BibTeX:
    @article{Tanaka2004,
      author = {Tanaka, SC and Doya, K and Okada, G and Ueda, K and Okamoto, Y and Yamawaki, S},
      title = {Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops},
      journal = {NATURE NEUROSCIENCE},
      year = {2004},
      volume = {7},
      number = {8},
      pages = {887-893},
      doi = {{10.1038/nn1279}}
    }
    
    TANDA, G., CARBONI, E., FRAU, R. & DICHIARA, G. INCREASE OF EXTRACELLULAR DOPAMINE IN THE PREFRONTAL CORTEX - A TRAIT OF DRUGS WITH ANTIDEPRESSANT POTENTIAL {1994} PSYCHOPHARMACOLOGY
    Vol. {115}({1-2}), pp. {285-288} 
    article  
    Abstract: Drugs differing in their primary mechanism of action but having in common the ability to act as antidepressants such as fluoxetine (10 mg/kg SC), clomipramine (10 mg/kg IP), imipramine (10 mg/kg IP), desipramine (10 mg/kg IP) and (+/-)8-OHDPAT (0.03 mg/kg SC) increase extracellular concentrations of dopamine in the rat prefrontal cortex but not in the medial nucleus accumbens. Buspirone (1 mg/kg SC) increased dopamine both in the prefrontal cortex and in the nucleus accumbens. Extracellular 5HT was increased by fluoxetine, clomipramine and imipramine but not by desipramine while 8-OHDPAT and buspirone decreased it. These results raise the possibility that the property of stimulating dopamine transmission in the prefrontal cortex has a role in the antidepressant properties of these drugs.
    BibTeX:
    @article{TANDA1994,
      author = {TANDA, G and CARBONI, E and FRAU, R and DICHIARA, G},
      title = {INCREASE OF EXTRACELLULAR DOPAMINE IN THE PREFRONTAL CORTEX - A TRAIT OF DRUGS WITH ANTIDEPRESSANT POTENTIAL},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1994},
      volume = {115},
      number = {1-2},
      pages = {285-288}
    }
    
    Tanda, G., Pontieri, F. & DiChiara, G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu 1 opioid receptor mechanism {1997} SCIENCE
    Vol. {276}({5321}), pp. {2048-2050} 
    article  
    Abstract: The effects of the active ingredient of Cannabis, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), and of the highly addictive drug heroin on in vivo dopamine transmission in the nucleus accumbens were compared in Sprague-Dawley rats by brain microdialysis, Delta(9)-THC and heroin increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2. SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of Delta(9)-THC but not those of heroin. Naloxone, a generic opioid antagonist, administered systemically, or naloxonazine, an antagonist of mu(1) opioid receptors, infused into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopa mine transmission. Thus, Delta(9)-THC and heroin exert similar effects on mesolimbic dopamine transmission through a common mu(1) opioid receptor mechanism located in the ventral mesencephalic tegmentum.
    BibTeX:
    @article{Tanda1997,
      author = {Tanda, G and Pontieri, FE and DiChiara, G},
      title = {Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu 1 opioid receptor mechanism},
      journal = {SCIENCE},
      year = {1997},
      volume = {276},
      number = {5321},
      pages = {2048-2050}
    }
    
    TAYLOR, J. & ROBBINS, T. 6-HYDROXYDOPAMINE LESIONS OF THE NUCLEUS-ACCUMBENS, BUT NOT OF THE CAUDATE-NUCLEUS, ATTENUATE ENHANCED RESPONDING WITH REWARD-RELATED STIMULI PRODUCED BY INTRAACCUMBENS D-AMPHETAMINE {1986} PSYCHOPHARMACOLOGY
    Vol. {90}({3}), pp. {390-397} 
    article  
    BibTeX:
    @article{TAYLOR1986,
      author = {TAYLOR, JR and ROBBINS, TW},
      title = {6-HYDROXYDOPAMINE LESIONS OF THE NUCLEUS-ACCUMBENS, BUT NOT OF THE CAUDATE-NUCLEUS, ATTENUATE ENHANCED RESPONDING WITH REWARD-RELATED STIMULI PRODUCED BY INTRAACCUMBENS D-AMPHETAMINE},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1986},
      volume = {90},
      number = {3},
      pages = {390-397}
    }
    
    TAYLOR, J. & ROBBINS, T. ENHANCED BEHAVIORAL-CONTROL BY CONDITIONED REINFORCERS FOLLOWING MICROINJECTIONS OF D-AMPHETAMINE INTO THE NUCLEUS ACCUMBENS {1984} PSYCHOPHARMACOLOGY
    Vol. {84}({3}), pp. {405-412} 
    article  
    BibTeX:
    @article{TAYLOR1984,
      author = {TAYLOR, JR and ROBBINS, TW},
      title = {ENHANCED BEHAVIORAL-CONTROL BY CONDITIONED REINFORCERS FOLLOWING MICROINJECTIONS OF D-AMPHETAMINE INTO THE NUCLEUS ACCUMBENS},
      journal = {PSYCHOPHARMACOLOGY},
      year = {1984},
      volume = {84},
      number = {3},
      pages = {405-412}
    }
    
    TEICHER, M., ANDERSEN, S. & HOSTETTER, J. EVIDENCE FOR DOPAMINE-RECEPTOR PRUNING BETWEEN ADOLESCENCE AND ADULTHOOD IN STRIATUM BUT NOT NUCLEUS-ACCUMBENS {1995} DEVELOPMENTAL BRAIN RESEARCH
    Vol. {89}({2}), pp. {167-172} 
    article  
    Abstract: Postnatal development of dopamine D-1 and D-2 receptor families in striatum and nucleus accumbens of rats was studied at 25, 35, 40, 60, 80, 100 and 120 days using autoradiography. These ages were selected to test the hypothesis that dopamine receptors were overproduced prior to puberty (day 40), and pruned back to adult levels thereafter. This hypothesis was confirmed in striatum but not nucleus accumbens. D-1 receptor B-max ([H-3]SCH-23390) peaked at 40 days, with levels 67 +/- 21% greater than at 25 days. However, B-max levels were at least 35% lower at 60-120 days than at 40 days. Similarly, D-2 receptor numbers ([H-3]YM-09151-2) increased 144 +/- 26% between 25 and 40 days, but were reduced by 34-38% between 60-120 days. In contrast, D-1 and D-2 receptor B-max increase approximately 150% between 25 and 40 days in nucleus accumbens, levels fell slightly at 60 or 80 days, but were no different at 100 and 120 days then they were at 40 days. These findings suggest that these two major dopamine target regions follow different developmental strategies, and this has implications for etiological theories of schizophrenia that focus on anomalous receptor pruning.
    BibTeX:
    @article{TEICHER1995,
      author = {TEICHER, MH and ANDERSEN, SL and HOSTETTER, JC},
      title = {EVIDENCE FOR DOPAMINE-RECEPTOR PRUNING BETWEEN ADOLESCENCE AND ADULTHOOD IN STRIATUM BUT NOT NUCLEUS-ACCUMBENS},
      journal = {DEVELOPMENTAL BRAIN RESEARCH},
      year = {1995},
      volume = {89},
      number = {2},
      pages = {167-172}
    }
    
    TERWILLIGER, R., BEITNERJOHNSON, D., SEVARINO, K., CRAIN, S. & NESTLER, E. A GENERAL ROLE FOR ADAPTATIONS IN G-PROTEINS AND THE CYCLIC-AMP SYSTEM IN MEDIATING THE CHRONIC ACTIONS OF MORPHINE AND COCAINE ON NEURONAL FUNCTION {1991} BRAIN RESEARCH
    Vol. {548}({1-2}), pp. {100-110} 
    article  
    Abstract: Previous studies have shown that chronic morphine increases levels of the G-protein subunits G(i-alpha) and G(o-alpha), adenylate cyclase, cyclic AMP-dependent protein kinase, and certain phosphoproteins in the rat locus coeruleus, but not in several other brain regions studied, and that chronic morphine decreases levels of G(i-alpha) and increases levels of adenylate cyclase in dorsal root ganglion/spinal cord (DRG-SC) co-cultures. These findings led us to survey the effects of chronic morphine on the G-protein/cyclic AMP system in a large number of brain regions to determine how widespread such regulation might be. We found that while most regions showed no regulation in response to chronic morphine, nucleus accumbens (NAc) and amygdala did show increases in adenylate cyclase and cyclic AMP-dependent protein kinase activity, and thalamus showed an increase in cyclic AMP-dependent protein kinase activity only. An increase in cyclic AMP-dependent protein kinase activity was also observed in DRG-SC co-cultures. Morphine regulation of G-proteins was variable, with decreased levels of G(i-alpha) seen in the NAc, increased levels of G(i-alpha) and G(o-alpha) in amygdala, and no change in thalamus or the other brain regions studied. Interestingly, chronic treatment of rats with cocaine, but not with several non-abused drugs, produced similar changes compared to morphine in G-proteins, adenylate cyclase, and cyclic AMP-dependent protein kinase in the NAc, but not in the other brain regions studied. These results indicate that regulation of the G-protein/cyclic AMP system represents a mechanism by which a number of opiate-sensitive neurons adapt to chronic morphine and thereby develop aspects of opiate tolerance and/or dependence. The findings that chronic morphine and cocaine produce similar adaptations in the NAc, a brain region important for the reinforcing actions of many types of abused substances, suggest further that common mechanisms may underlie psychological aspects of drug addiction mediated by this brain region.
    BibTeX:
    @article{TERWILLIGER1991,
      author = {TERWILLIGER, RZ and BEITNERJOHNSON, D and SEVARINO, KA and CRAIN, SM and NESTLER, EJ},
      title = {A GENERAL ROLE FOR ADAPTATIONS IN G-PROTEINS AND THE CYCLIC-AMP SYSTEM IN MEDIATING THE CHRONIC ACTIONS OF MORPHINE AND COCAINE ON NEURONAL FUNCTION},
      journal = {BRAIN RESEARCH},
      year = {1991},
      volume = {548},
      number = {1-2},
      pages = {100-110}
    }
    
    TESTA, C., STANDAERT, D., YOUNG, A. & PENNY, J. METABOTROPIC GLUTAMATE-RECEPTOR MESSENGER-RNA EXPRESSION IN THE BASAL GANGLIA SF THE RAT {1994} JOURNAL OF NEUROSCIENCE
    Vol. {14}({5, Part 2}), pp. {3005-3018} 
    article  
    Abstract: Metabotropic glutamate receptors (mGluRs) couple the actions of glutamate to intracellular second messenger systems through G-proteins. The mGluRs play an important role in the regulation of basal ganglia function. Ligand binding studies have revealed that the basal ganglia contain at least two pharmacological types of metabotropic binding sites. Agonists of mGluRs can affect both in vitro electrophysiologic responses of striatal neurons and motor behavior in vivo. Recently, cDNAs encoding five mGluRs have been cloned, each with distinct structural and pharmacological properties. In order to elucidate the function of these receptors in the biology of the extrapyramidal motor system, we have used in situ hybridization to examine the regional and cellular expression patterns of mGluR1-mGluR5 in the adult rat basal ganglia. In the striatum, all of these mGluRs were present in widely varying relative densities and cellular patterns. MGluR5 was particularly prominent, and exhibited a heterogeneous cellular distribution, with labeled and unlabeled populations of neurons. MGluR2 was expressed in a small population of large polygonal striatal neurons. The subthalamic nucleus was the only other basal ganglia structure that expressed mGluR2. Distinct cellular distributions of mGluR expression were also observed within the nucleus accumbens, globus pallidus, ventral pallidum, and substantia nigra pars reticulata. MGluR3 was expressed in glia in all basal ganglia structures, but was observed in neurons only in the striatum, substantia nigra pars reticulata, and very weakly in the subthalamic nucleus. Comparison of the restricted mGluR2 and mGluR3 mRNA distributions with that of metabotropic ligand binding sites supports a possible presynaptic location for these receptors in the basal ganglia. MGlUR1 was the only mGluR message prominently expressed in the dopaminergic neurons of the substantia nigra pars compacta, suggesting the involvement of this receptor in the regulation of dopamine release from nigrostriatal terminals.
    BibTeX:
    @article{TESTA1994,
      author = {TESTA, CM and STANDAERT, DG and YOUNG, AB and PENNY, JB},
      title = {METABOTROPIC GLUTAMATE-RECEPTOR MESSENGER-RNA EXPRESSION IN THE BASAL GANGLIA SF THE RAT},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1994},
      volume = {14},
      number = {5, Part 2},
      pages = {3005-3018}
    }
    
    Thiruchelvam, M., Richfield, E., Baggs, R., Tank, A. & Cory-Slechta, D. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: Implications for Parkinson's disease {2000} JOURNAL OF NEUROSCIENCE
    Vol. {20}({24}), pp. {9207-9214} 
    article  
    Abstract: Experimental evidence supporting 1,1'-dimethyl-4,4'-bipyridinium [paraquat (PQ)] as a risk factor for Parkinson's disease (PD) is equivocal. Other agricultural chemicals, including dithiocarbamate fungicides such as manganese ethylenebisdithiocarbamate [maneb (MB)], are widely used in the same geographical regions as paraquat and also impact dopamine systems, suggesting that mixtures may be more relevant etiological models. This study therefore proposed that combined PQ and MB exposures would produce greater effects on dopamine (DA) systems than would either compound administered alone. Male C57BL/6 mice were treated twice a week for 6 weeks with intraperitoneal saline, 10 mg/kg paraquat, 30 mg/kg maneb, or their combination (PQ 1 MB). MB, but not PQ, reduced motor activity immediately after treatment, and this effect was potentiated by combined PQ 1 MB treatment. As treatments progressed, only the combined PQ 1 MB group evidenced a failure of motor activity levels to recover within 24 hr. Striatal DA and dihydroxyphenylacetic acid increased 1-3 d and decreased 7 d after injections. Only PQ 1 MB reduced tyrosine hydroxylase (TH) and DA transporter immunoreactivity and did so in dorsal striatum but not nucleus accumbens. Correspondingly, striatal TH protein levels were decreased only by combined PQ 1 MB 5 d after injection. Reactive gliosis occurred only in response to combined PQ 1 MB in dorsal-medial but not ventral striatum. TH immunoreactivity and cell counts were reduced only by PQ 1 MB and in the substantia nigra but not ventral tegmental area. These synergistic effects of combined PQ 1 MB, preferentially expressed in the nigrostriatal DA system, suggest that such mixtures could play a role in the etiology of PD.
    BibTeX:
    @article{Thiruchelvam2000,
      author = {Thiruchelvam, M and Richfield, EK and Baggs, RB and Tank, AW and Cory-Slechta, DA},
      title = {The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: Implications for Parkinson's disease},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {2000},
      volume = {20},
      number = {24},
      pages = {9207-9214}
    }
    
    Thomas, M., Beurrier, C., Bonci, A. & Malenka, R. Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine {2001} NATURE NEUROSCIENCE
    Vol. {4}({12}), pp. {1217-1223} 
    article  
    Abstract: A compelling model of experience-dependent plasticity is the long-lasting sensitization to the locomotor stimulatory effects of drugs of abuse. Adaptations in the nucleus accumbens (NAc), a component of the mesolimbic dopamine system, are thought to contribute to this behavioral change. Here we examine excitatory synaptic transmission in NAc slices prepared from animals displaying sensitization 10-14 days after repeated in vivo cocaine exposure. The ratio of AMPA (alpha -amino-3-hydroxy-5-methyl-4- isoxazole propionic acid) receptor- to NMDA (N-methyl-D-aspartate) receptor-mediated excitatory postsynaptic currents (EPSCs) was decreased at synapses made by prefrontal cortical afferents onto medium spiny neurons in the shell of the NAc. The amplitude of miniature EPSCs at these synapses also was decreased, as was the magnitude of long-term depression. These data suggest that chronic in vivo administration of cocaine elicits a long-lasting depression of excitatory synaptic transmission in the NAc, a change that may contribute to behavioral sensitization and addiction.
    BibTeX:
    @article{Thomas2001,
      author = {Thomas, MJ and Beurrier, C and Bonci, A and Malenka, RC},
      title = {Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine},
      journal = {NATURE NEUROSCIENCE},
      year = {2001},
      volume = {4},
      number = {12},
      pages = {1217-1223}
    }
    
    Thompson, J., Thomas, N., Singleton, A., Piggott, M., Lloyd, S., Perry, E., Morris, C., Perry, R., Ferrier, I. & Court, J. D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele {1997} PHARMACOGENETICS
    Vol. {7}({6}), pp. {479-484} 
    article  
    Abstract: The relationship between a dopamine D2 receptor genetic polymorphism at the Taq1 A locus and the level of D2 receptor binding was investigated in normal, middle aged to elderly subjects with no psychiatric or neurological disorders. D2 receptor binding was measured by autoradiography in the caudate, putamen and nucleus accumbens, using the specific D2 receptor ligand [H-3]-raclopride. In a sample of 44 individuals, only one was homozygous for the A1 allele, 25 were homozygous for A2 and 18 were heterozygotes. The presence of one or two A1 alleles was associated with reduced D2 receptor binding in all areas of the striatum, reaching statistical significance in the ventral caudate and putamen (p = 0.01 and p = 0.044, respectively). This reduction was more marked in males than females, particularly in the putamen. A genetic predisposition to lower D2 receptor expression may increase susceptibility to neuroleptic medication or clinical symptoms that are associated with diseases involving dopaminergic pathology.
    BibTeX:
    @article{Thompson1997,
      author = {Thompson, J and Thomas, N and Singleton, A and Piggott, M and Lloyd, S and Perry, EK and Morris, CM and Perry, RH and Ferrier, IN and Court, JA},
      title = {D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele},
      journal = {PHARMACOGENETICS},
      year = {1997},
      volume = {7},
      number = {6},
      pages = {479-484}
    }
    
    TIBERI, M., JARVIE, K., SILVIA, C., FALARDEAU, P., GINGRICH, J., GODINOT, N., BERTRAND, L., YANGFENG, T., FREMEAU, R. & CARON, M. CLONING, MOLECULAR CHARACTERIZATION, AND CHROMOSOMAL ASSIGNMENT OF A GENE ENCODING A 2ND D1 DOPAMINE RECEPTOR SUBTYPE - DIFFERENTIAL EXPRESSION PATTERN IN RAT-BRAIN COMPARED WITH THE D1A RECEPTOR {1991} PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Vol. {88}({17}), pp. {7491-7495} 
    article  
    Abstract: Multiple D1 dopaminergic receptor subtypes have been postulated on the basis of pharmacological, biochemical, and genetic studies. We describe the isolation and characterization of a rat gene encoding a dopamine receptor that is structurally and functionally similar to the D1 dopamine receptor. The coding region, which is intronless, encodes a protein of 475 amino acids (M(r) 52,834) with structural features that are consistent with receptors coupled to guanine nucleotide-binding regulatory proteins. The expressed protein binds dopaminergic ligands and mediates stimulation of adenylyl cyclase with pharmacological properties similar to those of the D1 dopamine receptor. The gene encoding the human homologue of this receptor subtype is located to the short arm of chromosome 4 (4pl6.3), the same region as the Huntington disease gene. In striking contrast to the previously cloned D1 receptor, little or no mRNA for the receptor described here was observed in striatum, nucleus accumbens, olfactory tubercle, and frontal cortex. High levels of mRNA for this receptor were found in distinct layers of the hippocampus, the mammillary nuclei, and the anterior pretectal nuclei, brain regions that have been shown to exhibit little or no D1 dopamine receptor binding. On the basis of its properties we propose that this dopamine receptor subtype be called D1B.
    BibTeX:
    @article{TIBERI1991,
      author = {TIBERI, M and JARVIE, KR and SILVIA, C and FALARDEAU, P and GINGRICH, JA and GODINOT, N and BERTRAND, L and YANGFENG, TL and FREMEAU, RT and CARON, MG},
      title = {CLONING, MOLECULAR CHARACTERIZATION, AND CHROMOSOMAL ASSIGNMENT OF A GENE ENCODING A 2ND D1 DOPAMINE RECEPTOR SUBTYPE - DIFFERENTIAL EXPRESSION PATTERN IN RAT-BRAIN COMPARED WITH THE D1A RECEPTOR},
      journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
      year = {1991},
      volume = {88},
      number = {17},
      pages = {7491-7495}
    }
    
    TOTTERDELL, S. & SMITH, A. CONVERGENCE OF HIPPOCAMPAL AND DOPAMINERGIC INPUT ONTO IDENTIFIED NEURONS IN THE NUCLEUS ACCUMBENS OF THE RAT {1989} JOURNAL OF CHEMICAL NEUROANATOMY
    Vol. {2}({5}), pp. {285-298} 
    article  
    BibTeX:
    @article{TOTTERDELL1989,
      author = {TOTTERDELL, S and SMITH, AD},
      title = {CONVERGENCE OF HIPPOCAMPAL AND DOPAMINERGIC INPUT ONTO IDENTIFIED NEURONS IN THE NUCLEUS ACCUMBENS OF THE RAT},
      journal = {JOURNAL OF CHEMICAL NEUROANATOMY},
      year = {1989},
      volume = {2},
      number = {5},
      pages = {285-298}
    }
    
    TREVISAN, L., FITZGERALD, L., BROSE, N., GASIC, G., HEINEMANN, S., DUMAN, R. & NESTLER, E. CHRONIC INGESTION OF ETHANOL UP-REGULATES NMDAR1 RECEPTOR SUBUNIT IMMUNOREACTIVITY IN RAT HIPPOCAMPUS {1994} JOURNAL OF NEUROCHEMISTRY
    Vol. {62}({4}), pp. {1635-1638} 
    article  
    Abstract: We examined the effects of chronic ethanol exposure on the levels of N-methyl-D-aspartate receptor subunit 1 (NMDAR1) protein, an essential component of N-methyl-D-aspartate glutamate receptors, in rat brain. By immunoblotting procedures using a specific antibody for the NMDAR1 subunit, we found that ethanol dramatically up-regulated (by 65 NMDAR1 immunoreactivity in the hippocampus but not in the nucleus accumbens, cerebral cortex, or striatum. In contrast, ethanol did not alter the levels of glutamate receptor subunit (GLUR) 1 or GLUR2 protein, subunits that make up the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptor, in the hippocampus. Because ethanol can potentially influence many different neurotransmitter systems, we examined whether chronic treatment with several psychotropic drugs with different pharmacological profiles (cocaine, haloperidol, SCH 23390, imipramine, and morphine) could mimic the effect of ethanol. None of these agents increased hippocampal NMDAR1 subunit immunoreactivity after chronic administration. Increased NMDAR1 subunit levels in the hippocampus after chronic ethanol exposure may represent an important neurochemical substrate for some of the features associated with ethanol dependence and withdrawal.
    BibTeX:
    @article{TREVISAN1994,
      author = {TREVISAN, L and FITZGERALD, LW and BROSE, N and GASIC, GP and HEINEMANN, SF and DUMAN, RS and NESTLER, EJ},
      title = {CHRONIC INGESTION OF ETHANOL UP-REGULATES NMDAR1 RECEPTOR SUBUNIT IMMUNOREACTIVITY IN RAT HIPPOCAMPUS},
      journal = {JOURNAL OF NEUROCHEMISTRY},
      year = {1994},
      volume = {62},
      number = {4},
      pages = {1635-1638}
    }
    
    Trivedi, P., Yu, H., MacNeil, D., Van der Ploeg, L. & Guan, X. Distribution of orexin receptor mRNA in the rat brain {1998} FEBS LETTERS
    Vol. {438}({1-2}), pp. {71-75} 
    article  
    Abstract: The expression pattern of mRNA encoding two orexin receptors (OX1R and OX2R) in the rat brain was examined. OX1R and OX2R exhibited marked differential distribution. Within the hypothalamus, OX1R mRNA is most abundant in the ventromedial hypothalamic nucleus whereas OX2R is predominantly expressed in the paraventricular nucleus, High levels of OX1R mRNA were also detected in tenia tecta, the hippocampal formation, dorsal raphe, and locus coeruleus, OX2R mRNA is mainly expressed in cerebral cortex, nucleus accumbens, subthalamic and paraventricular thalamic nuclei, anterior pretectal nucleus. The presence of orexin receptor mRNA in the hypothalamus is in support of its proposed role in feeding regulation, Broad central distribution of orexin receptors may indicate additional functions for orexins, (C) 1998 Federation of European Biochemical Societies.
    BibTeX:
    @article{Trivedi1998,
      author = {Trivedi, P and Yu, H and MacNeil, DJ and Van der Ploeg, LHT and Guan, XM},
      title = {Distribution of orexin receptor mRNA in the rat brain},
      journal = {FEBS LETTERS},
      year = {1998},
      volume = {438},
      number = {1-2},
      pages = {71-75}
    }
    
    Trupp, M., Belluardo, N., Funakoshi, H. & Ibanez, C. Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS {1997} JOURNAL OF NEUROSCIENCE
    Vol. {17}({10}), pp. {3554-3567} 
    article  
    Abstract: Glial cell line-derived neurotrophic factor (GDNF), the most potent trophic factor yet described for both dopaminergic neurons of the substantia nigra and spinal motorneurons, has recently been shown to signal through a multireceptor complex composed of a novel glycosylphosphatidylinositol-anchored GDNF receptor-alpha (GDNFR-alpha) and the receptor tyrosine kinase product of the c-ret proto-oncogene (RET). Despite its importance, the individual expression patterns and the relationships between domains of expression of the different components of this trophic system are not understood. We show here by in situ hybridization that GDNF mRNA is expressed in the normal adult rat brain in several targets of substantia nigra neurons, including striatum, nucleus accumbens, thalamic nuclei, olfactory tubercle, hippocampus, cerebellum, and cingulate cortex as well as in the internal granular cell layer of the olfactory bulb. Within the basal ganglia we observe a pronounced segregation of regions expressing GDNF from those expressing GDNF receptors, suggesting that within these structures GDNF is functioning in its anticipated role as a target-derived trophic factor. In addition, the expression of GDNF and both GDNF receptors within the cerebellum, hippocampus, and olfactory bulb may indicate a paracrine mode of action. Importantly, we also see expression of RET mRNA in cellular populations within the cerebellum and the glomerular layer of the olfactory bulb, as well as in the subthalamic nucleus, which lack GDNFR-alpha expression, indicating that RET functions either independently of GDNFR-alpha or with GDNFR-alpha presented in trans. Conversely, GDNFR-alpha is widely expressed in many regions in which RET expression is absent, suggesting that GDNFR-alpha may associate with additional signaling receptors. Finally, RET and GDNFR-alpha show distinct patterns of regulated expression in the brain after kainic acid stimulation and in the sciatic nerve after nerve transection. Taken together these findings indicate that GDNF, RET, and GDNFR-alpha utilize multiple mechanisms to comprise physiologically relevant trophic circuits for different neuronal populations.
    BibTeX:
    @article{Trupp1997,
      author = {Trupp, M and Belluardo, N and Funakoshi, H and Ibanez, CF},
      title = {Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS},
      journal = {JOURNAL OF NEUROSCIENCE},
      year = {1997},
      volume = {17},
      number = {10},
      pages = {3554-3567}
    }
    
    Tsou, K., Brown, S., Sanudo-Pena, M., Mackie, K. & Walker, J. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system {1998} NEUROSCIENCE
    Vol. {83}({2}), pp. {393-411} 
    article  
    Abstract: Immunohistochemical distribution of cannabinoid receptors in the adult rat brain was studied using specific purified antibodies against the amino-terminus of the CB1 receptor. Our results generally agree well with the previous studies using CB1 receptor autoradiography and messenger RNA in situ hybridization. However, because of its greater resolution, immunohistochemistry allowed identification of particular neuronal cells and fibers that possess cannabinoid receptors. CB1-like immunoreactivity was found in axons, cell bodies and dendrites, where it appeared as puncta in somata and processes. Both intensely and moderately or lightly stained neurons were observed. The intensely stained neurons were dispersed and only occur in cortical structures including hippocampal formation and olfactory bulb. Moderately or lightly stained neurons were found in caudate-putamen and amygdala. In the hippocampal formation only intensely stained neurons were observed. The cell bodies of pyramidal neurons in CA1 and CA3 fields appeared to be unstained but surrounded by a dense plexus of immunoreactive fibers. The granule cells in the dentate area were also immunonegative. Many intensely stained neurons were located at the base of the granule cell layer. CB1-like immunoreactive neurons and fibers were also found in the somatosensory, cingulate, perirhinal, entorhinal and piriform cortices, in claustrum, amygdaloid nuclei, nucleus accumbens and septum. Beaded immunoreactive fibers were detected in periaqueductal gray, nucleus tractus solitarius, spinal trigeminal tract and nucleus, dorsal horn and lamina X of the spinal cord. A triangular cap-like mass of immunoreactivity was found to surround the basal part of the Purkinje cell body in the cerebellum. Only small, lightly stained cells were found in the molecular layer in the cerebellum close to the Purkinje cell layer. The CB1 receptor is widely distributed in the forebrain and has a more restricted distribution in the hindbrain and the spinal cord. It appears to be expressed on cell bodies, dendrites and axons. According to the location and morphology, many, but not all, CB1-like immunoreactive neurons appear to be GABAergic. Therefore, cannabinoids and cannabinoid receptors may play a role in modulating GABAergic neurons. (C) 1997 IBRO. Published by Elsevier Science Ltd.
    BibTeX:
    @article{Tsou1998,
      author = {Tsou, K and Brown, S and Sanudo-Pena, MC and Mackie, K and Walker, JM},
      title = {Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system},
      journal = {NEUROSCIENCE},
      year = {1998},
      volume = {83},
      number = {2},
      pages = {393-411}
    }
    
    Tzschentke, T. Measuring reward with the conditioned place preference paradigm: A comprehensive review of drug effects, recent progress and new issues {1998} PROGRESS IN NEUROBIOLOGY
    Vol. {56}({6}), pp. {613-672} 
    article  
    Abstract: This review gives an overview of recent findings and developments in research on brain mechanisms of reward and reinforcement from studies using the place preference conditioning paradigm, with emphasis on those studies that have been published within the last decade. Methodological issues of the paradigm (such as design of the conditioning apparatus, biased vs unbiased conditioning, state dependency effects) are discussed. Results from studies using systemic and local (intracranial) drug administration, natural reinforcers, and non-drug treatments and from studies examining the effects of lesions are presented. Papers reporting on conditioned place aversion (CPA) experiments are also included. A special emphasis is put on the issue of tolerance and sensitization to the rewarding properties of drugs. Transmitter systems that have been investigated with respect to their involvement in brain reward mechanisms include dopamine, opioids, acetylcholine, GABA, serotonin, glutamate, substance P, and cholecystokinin, the motivational significance of which has been examined either directly, by using respective agonist or antagonist drugs, or indirectly, by studying the effects of these drugs on the reward induced by other drugs. For a number of these transmitters, detailed studies have been conducted to delineate the receptor subtype(s) responsible for the mediation of the observed drug effects, particularly in the case of dopamine, the opioids, serotonin and glutamate. Brain sites that have been implicated in the mediation of drug-induced place conditioning include the `traditional' brain reward sites, ventral tegmental area and nucleus accumbens, but the medial prefrontal cortex? ventral pallidum, amygdala and the pedunculopontine tegmental nucleus have also been shown to play important roles in the mediation of place conditioning induced by drugs or natural reinforcers. Thus, although the paradigm has also been criticized because of some inherent methodological problems, it is clear that during the past decade place preference conditioning has become a valuable and firmly established and very widely used tool in behavioural pharmacology and addiction research. (C) 1998 Elsevier Science Ltd. All rights reserved.
    BibTeX:
    @article{Tzschentke1998,
      author = {Tzschentke, TM},
      title = {Measuring reward with the conditioned place preference paradigm: A comprehensive review of drug effects, recent progress and new issues},
      journal = {PROGRESS IN NEUROBIOLOGY},
      year = {1998},
      volume = {56},
      number = {6},
      pages = {613-672}
    }
    
    UNGERSTEDT, U. MICRODIALYSIS - PRINCIPLES AND APPLICATIONS FOR STUDIES IN ANIMALS AND MAN {1991} JOURNAL OF INTERNAL MEDICINE
    Vol. {230}({4}), pp. {365-373} 
    article  
    Abstract: Microdialysis is a technique for sampling the chemistry of the individual tissues and organs of the body, and is applicable to both animal and human studies. The basic principle is to mimic the function of a capillary blood vessel by perfusing a thin dialysis tube implanted into the tissue with a physiological liquid. The perfusate is analysed chemically and reflects the composition of the extracellular fluid with time due to the diffusion of substances back and forth over the membrane. Microdialysis is thus a technique whereby substances may be both recovered from and supplied to a tissue. The most important features of microdialysis are as follows: it samples the extracellular fluid, which is the origin of all blood chemistry; it samples continuously for hours or days without withdrawing blood; and it purifies the sample and simplifies chemical analysis by excluding large molecules from the perfusate. However, the latter feature renders the technique unsuitable for sampling large molecules such as proteins. The technique has been extensively used in the neurosciences to monitor neurotransmitter release, and is now finding application in monitoring of the chemistry of peripheral tissues in both animal and human studies.
    BibTeX:
    @article{UNGERSTEDT1991,
      author = {UNGERSTEDT, U},
      title = {MICRODIALYSIS - PRINCIPLES AND APPLICATIONS FOR STUDIES IN ANIMALS AND MAN},
      journal = {JOURNAL OF INTERNAL MEDICINE},
      year = {1991},
      volume = {230},
      number = {4},
      pages = {365-373}
    }
    
    Vanderschuren, L. & Kalivas, P. Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies {2000} PSYCHOPHARMACOLOGY
    Vol. {151}({2-3}), pp. {99-120} 
    article  
    Abstract: Rationale and objectives: Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala. Methods: The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and mu-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above. Results: The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine trans