Ronald E. See, Ph.D. - US grants

One of the most severe disorders of oral-motor function is tardive dyskinesia (TD). an iatrogenic syndrome which develops following the chronic administration of antipsychotic medication (neuroleptics). Treatment of TD and an understanding of the biological basis of the disorder remain unclear. Research directed at understanding the neurochemical processes involved in TD would enhance effective management of the disorder, assist in the development of safer neuroleptics, and provide information concerning the basic neural mechanisms involved in extrapyramidal control of oral-motor function. The series of studies proposed here will utilize a unique computerized method of analyzing orofacial activity in rats. This system provides detailed measures of the number and form of oral movements and has led to the development of a novel animal model of TD in which rats exhibit neuroleptic-induced oral dyskinesias similar in many respects to the human condition. Based on this rodent model, the present project will investigate the pharmacology of oral movements following both systemic and intracranial administration of a variety of drugs. Since most evidence suggests that neurochemical alterations in the basal ganglia underlie the orofacial dyskinesias of TD, these studies will focus on neurotransmitters known to mediate basal ganglia function, including dopamine, GABA, and acetylcholine, as well as the neuropeptides cholecystokinin and neurotensin. Following initial acute drug studies, appropriate drugs will then be used as pharmacological probes in rats exhibiting neuroleptic- induced oral dyskinesias. Other experiments will involve the use of in vivo microdialysis as a means of assessing dynamic changes in brain neurochemistry that occur in basal ganglia regions mediating orofacial movements. This approach will focus particularly on alterations in dopaminergic neurotransmission in chronic neuroleptictreated animals. These experiments address both the fundamental neuropharmacology of oral motor behaviors as well as neurochemical processes involved in pathological oral activity caused by neuroleptic treatment. The questions addressed in this proposal can only be answered by utilizing an animal model such as that proposed here.

DESCRIPTION: (Applicant's Abstract) Conditioned drug effects are believed to be involved in the relapse which often occurs following cessation of compulsive drug use. While a great deal of research has explored behavioral and neurochemical aspects of drug seeking behavior, there remains a lack of understanding of the fundamental relationship of conditioned drug effects to the neural circuitry affected by repeated drug exposure. Determining this relationship is critical to understanding the mechanisms of drug dependence and for the ultimate treatment of long term drug dependence. Recent studies from this laboratory have demonstrated conditioned cued responding following prolonged extinction from chronic cocaine self-administration in rats. In addition, it appears that the basolateral amygdala plays a key role in mediating conditioned cued effects, since lesions of this nucleus greatly attenuate conditioned cued recovery, without affecting maintenance of cocaine self-administration. The studies proposed here will utilize this model of conditioned drug effects to explore parameters of responding in the presence of conditioned reinforcers following extinction. Further experiments will lesion the dopaminergic inputs to the basolateral amygdala and utilize excitotoxic lesions of nuclei closely associated with the basolateral amygdala in order to determine if loss of these pathways also attenuates conditioned cued responding. Other experiments will attempt to potentiate conditioned responding by direct stimulation of glutamatergic and dopaminergic receptors in the basolateral amygdala. Finally, we will test the hypothesis that the basolateral amygdala is critical to conditioned responding across other classes of abused drugs by testing animals following chronic morphine self-administration. These experiments provide an integrated approach aimed at understanding the neural basis of long lasting conditioning effects produced during contingent drug administration. Information gained from this project will also provide direction for current development of medications aimed at treating craving and preventing relapse. the questions addressed in this proposal can only be answered by utilizing an animal model such as that proposed here.

Atypical anti-psychotic drugs (APDs) are primarily differentiated from typical APDs in that they possess a lower motor side effects profile. Experimental approaches to study "atypicality" have generally focused on cortical, striatal, and limbic dopamine terminal regions of the brain. However,, research findings on motor syndromes and psychosis also support the critical role of striatopallidal gamma-aminobutyric acid (GABA) pathways. Our specific global hypothesis is that decreases in pallidal GABA function mediate the atypical profile of certain APDs and may be a critical mechanism for the low incidence of motor side effects. Recent data from our laboratory has shown that typical APDs (e.g. haloperidol) produce motor side effects and increase GABA release in the globus pallidus, while atypical APDs (e.g. clozapine) produce minimal motor side effects and decrease GABA release in the globus pallidus. Furthermore, only clozapine has an effect on decreasing GABA in the ventral pallidum, a pallidal subregion believed to preferentially mediate "limbic" striatal output. The effect of atypical APDs may result form an inhibition of presynaptic release of GABA, since the density of nerve terminal GABA immunolabeling is increased after clozapine injection. This paradigm of altered GABA release in pallidal pathways could provide clues regarding the low incidence of motor side effects with atypical APDs and further our understanding of pallidal GABA in mediating atypical APD action. The series of studies proposed here will utilize a rodent model of acute and chronic APD administration to answer several questions. The first set of experiments will examine changes in extracellular and presynaptic pallidal GABA after systematic and site- specific administration of drugs with a high or low motor side effect profile. In order to test the possibility that 5-HT2 receptor subtypes play a role in mediating pallidal GABA function, a second series of experiments will assess 5-HT2A and 5-HT2C receptor agonism and antagonism on pallidal GABA function. In a final set of studies, pallidal GABA function and motor activity will be studied after prolonged periods of APD administration which are similar to the treatment durations utilized in psychotic patients. These studies will provide new insights on the mechanisms of action of APDs and provide a novel means of identifying putative atypical APDs. The information obtained will facilitate the development of optimal pharmacotherapy for mental disorders, particularly schizophrenia.

DESCRIPTION (provided by applicant): Relapse to drug use following abstinence is a significant impediment in the long-term treatment of drug abuse and dependence. Conditioned stimuli are believed to be critically involved in activating drug craving and relapse to compulsive drug-taking behavior. Although conditioned cues are now well recognized as a factor in relapse, there remains a lack of understanding of the fundamental neural circuitry that mediates relapse following withdrawal from chronic drug self-administration. Studies from our laboratory have demonstrated reinstatement of operant responding for drug-associated conditioned cues following chronic cocaine self-administration in rats. We showed that the basolateral amygdala (BLA) complex plays a key role in mediating the acquisition and expression of discrete conditioned cued effects, since inactivation of this nucleus greatly attenuates conditioned reinstatement, without affecting cocaine self-administration. Furthermore, reinstatement is dependent upon dopamine D1 receptors and also involves the central nucleus of the amygdala. In this competing renewal, studies are proposed to examine the neuropharmacological regulation of the BLA in conditioned reinstatement and to test the hypothesis that multiple neural pathways mediate different aspects of appetitive conditioning that occur during chronic drug self-administration. Specifically, we hypothesize that the BLA is a key regulator of discrete stimulus-reinforcer associations, but other brain regions, particularly areas of the prefrontal cortex and the nucleus accumbens, are critical for reinstatement evoked by discriminative conditioned stimuli that predict drug availability. In addition, we will extend the use of this relapse model across other classes of abused drugs by testing reinstatement of heroin-seeking behavior. These experiments provide an integrated approach aimed at understanding the neural basis of long-term conditioned associations produced by various drugs of abuse. Information gained from this project will provide direction for development of treatments for craving and for preventing relapse.

[unreadable] DESCRIPTION (provided by applicant): Methamphetamine abuse and dependence has rapidly become a major health problem throughout the United States. However, basic and clinical understanding of the neurobiology and treatment of methamphetamine addiction has lagged behind research on other drugs of abuse. This proposal endeavors to ameliorate this dearth of knowledge and proposes the development of a Translational Research in Addiction Center (TRAC) focused on the Clinical Neurobiology of Methamphetamine Dependence at the Medical University of South Carolina. Over the next four years, we will develop integrated, multidisciplinary teams to explore the neural pathways, cognitive and behavioral toxicities, and potential treatments for methamphetamine addiction in preparation for the submission of a P50 application. The TRAC is integrated around the common theme of translational research on methamphetamine addiction and will employ a well-established animal model of relapse in conjunction with a clinical laboratory and imaging center in an innovative collaboration designed to directly test hypotheses derived from the animal model in human subjects. In turn, information derived from methamphetamine dependent subjects in the clinical laboratory will inform and guide new directions in the animal models. The TRAC will determine the neurobiological adaptations mediating relapse and cognitive function at many levels of analysis, including cellular, physiological, and behavioral. We will also characterize in both preclinical and clinical models the neural circuitry of extinction training related to methamphetamine-associated cues and the relationship of cognitive deficits to drug-seeking behaviors. Importantly, neurobiological information derived from all of these projects will be used to develop rational pharmacological treatments designed to decrease relapse, improve methamphetamine-induced cognitive deficits, and facilitate extinction training. Thus, the TRAC will allow for the development of a multidisciplinary, integrated research team capable of conducting a multidimensional analysis of the clinical neurobiology underlying methamphetamine addiction and relapse. As part of the Center, a comprehensive plan has been established for mentoring new faculty and trainees and developing campus wide translational research in addiction. It is proposed that the integration and synergy inherent in the TRAC infrastructure that will be developed during the P20 funding period will provide the optimal opportunity for identifying novel pharmacological interventions that will be effective in treating methamphetamine addiction and reducing the individual and public health consequences of this devastating illness. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Relapse to cocaine use following prolonged abstinence is a significant impediment in the treatment of cocaine dependence. Several risk factors have been recognized as critical in triggering relapse to drug-seeking and drug-taking behavior in cocaine-dependent individuals. Human laboratory studies indicate that either cocaine-related cues or negative emotional stimuli can produce craving and physiological arousal. Likewise, animal models of relapse (e.g., the reinstatement of operant drug-seeking behavior) have clearly demonstrated that conditioned cues or exposure to acute stress elicits reinstatement of cocaine-seeking behavior in animals with a history of cocaine self-administration. These two risk factors, cues and stress, have been increasingly studied in regards to their ability to promote drug-seeking behavior and they represent the two best targets for relapse medication development. However, there has been minimal consideration of the interaction of these trigger factors in relapse, and almost no attempts to implement a translational approach to the empirical study of relapse and relapse prevention within a unified project. This proposed project will establish an interdisciplinary approach to study the primary risk factors for relapse (stress and cues) by using both an animal model of relapse and an established human clinical laboratory setting for assessing drug craving. In the animal model, acute stress exposure (foot shock stress or social stress) will be examined for the potentiative effects of stress on conditioned-cue (tone+light) responding on a previously cocaine-paired lever. In addition, we will test the effects of a novel dopamine partial agonist (aripiprazole) and a glutamate enhancing agent (modafinil) on stress, cue, and stress+cue induced reinstatement. In close parallel to the reinstatement experiments, we will directly assess stress, cue, and stress+cue interactions in a clinical laboratory setting. Specifically, HPA axis (ACTH, cortisol), physiological (heart rate, blood pressure, skin conductance), and subjective responses to acute stress (Trier Social Stress Test) or no stress followed by cocaine-related cue reactivity (self-reported drug craving) will be determined in cocaine-dependent individuals. As in the reinstatement model experiments, subjects will receive aripiprazole, modafinil, or placebo control prior to testing for stress and cue reactivity. In both the animal model and the human laboratory, we predict that stress exposure will potentiate responding to cocaine-paired cues and that craving and relapse will be attenuated by aripiprazole or modafinil. In summary, this project will: a) provide a unique interdisciplinary approach to bridge the gap between an established animal model of relapse with a clinical laboratory paradigm that will directly test the interaction of stress and cues in relapse, and b) simultaneously assess putative pharmacotherapies in both the animal model and the human laboratory for the treatment of cocaine addiction.

8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo,exo))-; Abstinence; Abuse, Cocaine; Addiction, Cocaine; Animal Husbandry; Animals; Behavior; Behavior assessment; Behavioral; Cathetergram; Catheterization; Cocaine; Cocaine Abuse; Cocaine Dependences; Common Rat Strains; Dependence; Dependences, Cocaine; Dose; Drug usage; Drugs; Electrophysiology; Electrophysiology (science); Equilibrium; Evaluation; Extinction; Extinction (Psychology); Foundations; Goals; Husbandries, Animal; Individual; Instrumental Learning; Intravenous; Investigators; Lead; Mammals, Rats; Medication; Methods and Techniques; Methods, Other; Modeling; Neurobiology; Neurophysiology / Electrophysiology; Operant Conditioning; Operant Conditionings; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Procedures; Rat; Rattus; Relapse; Research; Research Personnel; Researchers; Role; SCHED; Schedule; Self Administration; Self-Administered; Site; Standards; Standards of Weights and Measures; Stimulus; Techniques; Training; Withdrawal; addiction; balance; balance function; behavioral assessment; behavioral extinction; brain tissue; design; designing; desire; drug reinforcement; drug seeking behavior; drug use; drug/agent; experience; heavy metal Pb; heavy metal lead; instrumental conditioning; neurobiological; size; social role

Relapse to drug use following periods of abstinence is a significant impediment in the long-term treatment of cocaine dependence. Environmental stimuli or contexts previously associated with drug use or priming doses of the abused drug can initiate relapse to compulsive drug-seeking and drug-taking behaviors. Project 4 will take intervention strategies identified through the NARC projects aimed at reducing relapse to cocaine-seeking and systematically test compounds that will hopefully show significant and selective attenuation of cocaine-seeking in the relapse model. The advantages of having such a project within the NARC include: a) the ability to use standardized procedures through the NARC Animal Core of cocaine selfadministration and reinstatement, b) testing acute and chronic drug treatment protocols that inhibit cocaineseeking that can be further used in other NARC projects to assess the validity of cocaine-induced neuroplasticity for drug target development, and c) integrating the NARC preclinical animal model of relapse with potential clinical projects in the NARC Pilot Core as a transition to clinical assessment of promising pharmacotherapies. Project 4 will initially focus on a few selected strategies of drug intervention by targeting dopaminergic activity via a partial DA receptor agonist, enhancement of glutamatergic homeostasis, and antagonism of the orexin receptor. The proposed experiments will assess the effects of drug intervention after varied periods of cocaine-taking history, during and after extinction training, following abstinence in the absence of extinction, and in response to both conditioned cues and cocaine priming injections. Additional experiments will determine the effects of test compounds on ongoing cocaine-taking and responding for non-drug reinforcement (i.e., food). Since the focus of Project 4 will be the assessment of compounds that can be quickly applied in a clinical environment, we will initially focus on systemically available, approved drugs for use in humans. However, in years 4-5 of the proposed NARC renewal, we intend to take identified compounds from other NARC Projects that can be thoroughly assessed using the relapse model. In summary, Project 4 will provide for the systematic examination of testable drug interventions derived from studies within the NARC. Other projects within the NARC, in particular Project 1, will identify future targets of intervention as anti-relapse medications. By applying a seamless model of testing in conjunction with the NARC Animal Core, we will establish a template for the testing of putative medications as they are derived from NARC projects to serve as a bridge to clinical testing of such agents through the NARC Pilot Core. The results from these integrated studies will hopefully lead to useful pharmacotherapeutic agents for the

8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo,exo))-; Abstinence; Acetylcysteine; Acetylin; Address; Adverse effects; Airbron; Allen &Hanburys Brand of Acetylcysteine; Aminoacetic Acid; Animal Model; Animal Models and Related Studies; Animals; Attenuated; Behavior; Benzeneethanamine, N,alpha-dimethyl-, (S)-; Brain; Bristol-Myers Squibb Brand of Acetylcysteine; Bristol-Myers Squibb Brand of Acetylcysteine Sodium Salt; Broncholysin; Brunac; Cephalon brand of modafinil; Chronic; Clinical; Cocaine; Cognition; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive deficits; Cognitive function abnormal; Common Rat Strains; Condition; Crystal Meth; Cues; Cycloserine; Deoxyephedrine; Dependence; Desoxyephedrine; Development; Disturbance in cognition; Drug Abuse Detection; Drug Abuse Screening; Drug Abuse Testing; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Drug Therapy; Drug usage; Drugs; Encephalon; Encephalons; Exposure to; Extinction; Extinction (Psychology); Fabrol; Fluatox; Fluimucetin; Fluimucil; Fluprowit; Glutamates; Glycine; Goals; History; Human; Human, General; Impaired cognition; Injection of therapeutic agent; Injections; Inpharzam Brand of Acetylcysteine; Investigators; L-Alpha-acetamido-beta-mercaptopropionic Acid; L-Glutamate; Laboratories; Laboratory Procedures; Lead; Lesion; Mammals, Rats; Man (Taxonomy); Man, Modern; Measurement; Medication; Mercapturic Acid; Methamphetamine; Methylamphetamine; Modafinil; Modeling; Muco Sanigen; Mucocedyl; Mucolator; Mucolyticum; Mucomyst; Mucosolvin; Mucret; N-Acetyl Cysteine; N-Acetyl-L-cysteine; N-Acetylcysteine; N-Methyl-D-Aspartate Receptors; N-Methylamphetamine; N-acetyl-3-mercaptoalanine; NAC; NAC Zambon; NMDA Receptor-Ionophore Complex; NMDA Receptors; Nature; Neo-Fluimucil; Nervous System, Brain; Neurobiology; Optipect Hustengetr??nk; Parvolex; Pb element; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacotherapy; Prevention of relapse; Procedures; Process; Produpharm Lappe Brand of Acetylcysteine; Provigil; R-4-Amino-3-isoxazolidinone; Rat; Rattus; Receptors, N-Methylaspartate; Recording of previous events; Relapse; Research; Research Personnel; Researchers; Resistance; Respaire; Risk Factors; Roberts Brand of Acetylcysteine; Role; Self Administration; Site; Substance Abuse Detection; Substance Abuse Testing; Testing; Thiemann Brand of Acetylcysteine; Time; Tixair; Treatment Side Effects; UPSA Brand of Acetylcysteine; Withdrawal; Work; Zambon Brand of Acetylcysteine; Zyma Brand of Acetylcysteine; abused drugs; addiction; base; behavioral extinction; benzhydrylsulfinylacetamide; cognitive dysfunction; cognitive function; cognitive loss; cognitively impaired; desire; disorder later incidence prevention; drug of abuse; drug seeking behavior; drug use; drug/agent; drugs abused; drugs of abuse; experience; heavy metal Pb; heavy metal lead; human subject; improved; model organism; neurobiological; new approaches; novel; novel approaches; novel strategies; novel strategy; object recognition; pre-clinical; preclinical; prevent; preventing; prevention of disease recurrence; prevention of disorder recurrence; prevention of later incidences of a disorder; prevention of recurrence; receptor function; resistant; side effect; social role; therapy adverse effect; translational approach; treatment adverse effect

DESCRIPTION (provided by applicant): Relapse to drug use following abstinence is a significant impediment in the long-term treatment of drug dependence. Environmental stimuli or contexts previously associated with drug use can initiate relapse to compulsive drug-seeking and drug-taking behaviors. Reinstatement of responding for drug-associated conditioned cues, both discrete and contextual, following chronic drug self-administration has been demonstrated in rats. Although the role of conditioned cues is well recognized as a factor in relapse, only recently has the fundamental neural circuitry of relapse to various drugs of abuse been explored in detail. Using an extinction/reinstatement model of relapse, the role of the basolateral amygdala complex has been shown to be critical in the acquisition, consolidation, and expression of drug-cue associations that drive relapse. Furthermore, the circuitry of conditioned-cued reinstatement engages a network of brain nuclei that include discrete subregions of the prefrontal cortex and nucleus accumbens. Although extinction/reinstatement paradigms allow investigators to isolate specific features of stimuli that elicit relapse, human addicts generally do not undergo explicit extinction training upon cessation of drug use. Recent studies from our laboratory suggest that activation of the neural circuitry underlying relapse to drug-seeking after abstinence from the drug and the drug-paired environment is uniquely different from that engaged following explicit extinction training. These findings have implicated a significant role of the dorsolateral caudate-putamen (dlCPu) in mediating relapse following abstinence. In this competing renewal application, studies are proposed to test the global hypothesis that neuroadaptive changes in the dlCPu underlie habitual drug-seeking following abstinence from chronic cocaine self-administration. Specifically, we hypothesize that the dlCPu is a key regulator of habit learning that drives compulsive drug-seeking during relapse after abstinence. These changes are hypothesized to involve a change in neuronal activity of the dlCPu as manifested by changes in specific dopamine and glutamate receptor-mediated cell signaling cascades and increased dopamine and glutamate release in the dlCPu during relapse. These experiments provide an integrated approach employing behavioral, molecular biological, and neurochemical techniques aimed at understanding the neuronal bases of long-term conditioned associations produced during and after chronic cocaine self-administration. Information gained from this project will provide direction for development of anti-relapse medications for the treatment of cocaine dependence, as well as other drugs of abuse.

DESCRIPTION (provided by applicant): Methamphetamine addiction constitutes a serious and growing drug abuse problem in the United States. To date, there has not been a national conference devoted to the basic and clinical neurobiology of methamphetamine addiction. The proposed Translational Research in Methamphetamine Addiction conference is planned for July of 2010 and is co-sponsored by two NIDA-supported methamphetamine research centers: the Translational Research in Addiction Center at the Medical University of South Carolina and the Center for Translational Research of Addiction at the University of California, Los Angeles. This conference will have broad appeal to addiction researchers and will provide a catalyst for research interactions centered on the basic and clinical neurobiology of methamphetamine abuse and dependence. The topics and organizational format of the meeting will allow cross fertilization of expertise in areas that are critical to a comprehensive exploration of methamphetamine addiction, including pharmacology, neurobiology, animal models, clinical assessment, brain imaging, and novel treatment. The combination of basic and clinical researchers at this conference will allow unique interdisciplinary levels of communication and encourage the future emergence of new research, training, and treatment opportunities. The preclinical presentations will juxtapose closely with the clinical presentations and thereby facilitate the capacity to unite discoveries emerging from different research approaches into a coherent understanding of the clinical neurobiological basis of methamphetamine addiction. Furthermore, young investigators will have excellent opportunities at the conference to interact with leading methamphetamine researchers from around the country. The thematic integration of the conference will focus multiple dimensions of research activity with the goal of providing translational coverage in the field of methamphetamine addiction, dysfunction, and treatments. As such, the conference will be the first of its kind to provide a forum on methamphetamine addiction that is clearly aligned with the NIH Roadmap Initiative. PUBLIC HEALTH RELEVANCE: The proposed Translational Research in Methamphetamine Addiction conference is planned for July of 2010 and is co-sponsored by the MUSC Translational Research in Addiction Center and the UCLA Center for Translational Research of Addiction. The conference will include a comprehensive exploration of methamphetamine addiction at the preclinical and clinical levels. The thematic integration of the conference will offer addiction researchers a unique forum on current findings in methamphetamine addiction.

DESCRIPTION (provided by applicant): Chronic methamphetamine (meth) self-administration in rats provides a translational animal model for the study of cognitive and motivational deficits of meth addiction in humans. This project consists of a multidisciplinary approach to study meth-induced cognitive and motivational dysfunctions, determine their critical neurobiological substrates in cortical glutamatergic circuitry, and reverse meth-induced changes with chronic pharmacotherapy. Specifically, we will first assess object recognition memory deficits in novel object and object-in-place recognition memory in rats with a history of chronic meth self-administration, withdrawal, and renewed drug-seeking. We hypothesize that chronic meth intake will negatively affect memory performance and that deficits will be related to altered glutamate receptors (AMPA, NMDA, mGluR2/3, and mGluR5) and glutamate receptor dependent neuron activity in the prefrontal and perirhinal cortices. We will also examine the ability of potential cognitive enhancers to reverse chronic meth-induced memory deficits by acting on glutamate receptors. We predict that chronic modafinil or an mGluR5 allosteric modulator (CDPPB) will reverse meth-induced cognitive deficits and reduce drug-seeking by acting on the aforementioned substrates. Finally, we will determine the impact of chronic meth SA on prefrontal cortex dependent attentional processing using a novel operant based attentional set-shifting task. These studies are significant in that they will provide novel insighs on chronic meth-induced changes in cognitive performance and neuroplasticity using a multifaceted assembly of behavioral, neurochemical, and neurophysiological techniques in a translationally relevant model of meth addiction. Ultimately, this project will advance our understanding of the neural substrates of cognitive deficits in meth addiction and the development of neurobiologically derived treatments for meth addiction. PUBLIC HEALTH RELEVANCE: The major goals of this project are to study the neurobiology of chronic meth-induced cognitive deficits and relapse, and the attenuation of these factors by targeting cortical glutamate receptor function. We have closely aligned the animal model with important clinical issues both conceptually (e.g., cognitive deficits linked to meth addiction) and methodologically (e.g., analogous behavioral assessments). These studies will provide relevant and insightful data on the neurobiology of meth addiction and guidance to experimental and treatment approaches in human meth addicts.