Roger D. Spealman - US grants

Methylxanthines and benzodiazepines are among the most widely used behaviorally active drugs in contemporary society. Research is proposed to systematically investigate pharmacological and environmental factors that mediate their effects on behavior. The behavioral actions of methylxanthines will be investigated by: 1) determining their effects on schedule-controlled behavior of monkeys under conditions in which caffeine produces marked increases in response rate, 2) directly comparing their effects with those of prototypical psychomotor-stimulant drugs, 3) determining their effects in combination with selected derivatives of adenosine that block methylxanthine-induced increases in responding, and 4) evaluating their reinforcing effects under conditions in which caffeine maintains persistent self-administration. The behavioral actions of benzodiazepines and of newly developed drugs with putative antianxiety activity will be investigated by: 1) determining their effects on schedule-controlled behavior under conditions that distinguish antiznxiety drugs from other pharmacologic classes, 2) evaluating their stimulus effects under conditions in which benzodiazepines exert discriminative control over behavior, and 3) determining their effects in combination with selective benzodiazepine antagonists. The interactions between antianxiety drugs, methylxanthines, and derivatives of adenosine will be investigated under conditions in which methylxanthines enhance and adenosine derivatives block the characteristic effects of benzodiazepines. The proposed studies will provide needed information about how methylxanthines and benzodiazepines alter and control behavior.

The objective of research proposed in this request for an ADAMHA RSDA (Level II) is to investigate pharmacological and environmental factors that determine how drugs alter and control behavior. Systematic studies are proposed to investigate the behavioral actions of caffeine and related methylxanthines, of benzodiazepines and novel anxiolytic drugs, and of chronically administered cocaine and phencyclidine. The behavioral actions of methylxanthines will be studied by determining: 1) their effects on schedule-controlled behavior under conditions in which caffeine produces consistent increases in response rate, 2) their effects in combination with metabolically stable analogs of adenosine, which have actions opposing those of methylxanthines at adenosine receptors, and 3) their reinforcing effects under conditions in which caffeine maintains persistent self- administration. The effects of methylxanthines will be compared directly with those of other psychomotor-stimulant drugs including cocaine and amphetamine. The behavioral actions of novel drugs with anxiolytic potential will be studied by determining: 1) their effects under conditions that distinguish antianxiety agents from other pharmacological classes, 2) their effects in combination with benzodiazepine antagonists and full agonists, and 3) their effects in combination with methylxanthines and adenosine agonists, which alter the effects of benzodiazepines in qualitatively different ways. The effects of novel drugs will be compared directly with those of prototypical benzodiazepines and other anxiolytics. The effects of chronically administered cocaine and phencyclidine will be studied by determining: 1) how continuous exposure affects behavior maintained by self- administered drugs and other consequences and 2) how such exposure alters the behavioral effects of drugs that may be used illicitly in conjunction with cocaine or phencyclidine. The proposed studies will provide needed quantitative information about the behavioral effects of drugs used persistently in contemporary society.

The objectives of the proposed research are to develop improved molecular probes for specific cocaine recognition sites in brain and to provide fundamental information on the neuropharmacology of these sites in relation to cocaine abuse. Although [3H]cocaine has been a useful tool for characterizing cocaine recognition sites in tissue preparations with high site density, its relatively low affinity and rapid dissociation rate limit its suitability as a molecular probe for further research (e.g., determining regional distribution and labeling solubilized material). Recent studies in our laboratory have revealed that selected fluorophenyltropane analogs of cocaine and phenylindan derivatives have considerably greater affinity for cocaine recognition sites than does cocaine itself. These drugs will be used as precursors to develop novel radioligands and photoaffinity probes for cocaine recognition sites. Candidate drugs first will be assessed for cocaine-like biological activity in vitro by conducting competition studies with specifically bound C3H]cocaine in brain membranes of monkeys and in vivo by determining their effects on schedule-controlled behavior, their substitution for cocaine in drug-discrimination experiments, and their capacity to maintain i.v. self-administration in monkeys. Drugs with full cocaine-like activity will be tritiated, and binding sites labeled by the novel probes will be characterized in brain membranes. Radioligands with improved affinity and dissociation rates subsequently will be used to assess regional distribution of sites by quantitative autoradiography. The novel radioligands also will be used to characterize binding sites in solubilized membranes from selected brain regions. Lastly, photoaffinity probes based on the novel ligands will be developed and used to investigate the molecular structure of the recognition-site complex. The proposed research will provide needed information relevant for isolating cocaine receptors and for developing rational approaches to the pharmacological management of cocaine abuse.

Research is proposed to investigate jointly the behavioral and neurochemical effects of cocaine and related drugs in non-human primates. Quantitative studies will be conducted to determine the actions of cocaine, cocaine analogs and metabolites, other psychomotor-stimulant drugs, and selective monoamine transport inhibitors. Correspondence between empirical relations obtained in these coordinated studies will serve as a basis for identification of neural targets mediating the behavioral effects and abuse of cocaine. The efficacy of potential antagonists for cocaine will also be determined quantitatively in behavioral experiments. One major objective will be to determine the effects of full dose ranges of cocaine-related drugs on three types of behavior under schedules control. Stimulant effects of drugs will be assessed in monkeys responding under fixedinterval schedules involving different consequences. Interoceptive effects will be evaluated using drug-discrimination procedures involving cocaine and the selective dopamine transport inhibitor GBR 12909. Abuse liability will be investigated using i.v. drug self-administration techniques. A second objective will be to determine the effects of full concentration ranges of cocaine- related drugs at pharmacologically relevant binding sites for cocaine and uptake sites for dopamine in vitro. High, moderate and low affinity binding sites for 3H-cocaine will be characterized in membranes prepared from monkey caudate-putamen and nucleus accumbens. Parallel studies will be conducted for dopamine uptake by labeling the transporter with 3H-GBR 12935 in membranes and by determining accumulation of 3H-dopamine in slices. Binding sites for 3H-cocaine and 3H-GBR 12935 will be solubilized and evaluated for drug binding profiles, recovery and molecular weight to determine relationships between cocaine binding and dopamine transport sites. A third objective will be to determine the effectiveness of novel dopamine antagonists and adenosine analogs in counteracting the behavioral effects of cocaine. Drugs differing widely in affinity for dopamine D1 and D2 and adenosine Al and A2 receptors will be studied over a range of doses to evaluate their potential as antagonists of the stimulant, interoceptive and reinforcing effects of cocaine.

There is now compelling evidence for a functional link between cocaine's indirect dopamine (DA) agonist properties and its abuse-related effects in animals and humans. Based on such findings, several DA agonists and antagonists have been proposed as candidate medications to serve either as pharmacological replacements for cocaine or as functional cocaine antagonists. However, no broadly effective pharmacotherapy for cocaine abuse has yet been identified, prompting exploration of alternative treatment strategies. One such strategy involves the use of a relatively new class of DA drugs, the DA partial agonists. Because of their dual agonist-like and antagonist-like properties, DA partial agonists could have important therapeutic advantages over conventional DA antagonists or full agonists, along with less restrictive side-effects and low abuse liability. Research proposed in this application will establish the agonist efficacy of selective DA partial agonists in vitro and in vivo and evaluate their potential utility for treating cocaine abuse and relapse in relevant non-human primate models. In vitro studies will determine the capacity of D/1 and D/2 partial agonists to either stimulate or inhibit adenylyl cyclase activity in squirrel monkey striatal tissue. Corresponding in vivo studies in the same species will: 1) characterize the agonist-like and antagonist-like behavioral effects of D/1 and D/2 partial agonists, 2) establish efficacy relationships by quantifying interactions of these drugs with selective DA antagonists and full agonists and 3) identify potential extrapyramidal and sedative side-effects. Evaluation of D/1 and D/2 partial agonists as pharmacotherapies for cocaine abuse will determine their capacity to modulate the effects of cocaine in: 1) monkeys trained to discriminate different doses of cocaine from vehicle, 2) monkeys trained to self- administer cocaine under a second-order schedule of i.v. drug injection, and 3) monkeys whose drug-seeking behavior is extinguished and subsequently reinstated by cocaine priming and cocaine paired stimuli. Additional studies will determine the selectivity of promising drugs to modulate cocaine-maintained versus food-maintained behavior and the degree to which the cocaine-modulating effect of these drugs are retained as the dose of cocaine is increased. The results will provide relevant information for establishing functional relationships between agonist efficacy and the cocaine-modulating effects of DA partial agonists and for identifying candidate medications to combat cocaine abuse and relapse.

substance abuse related disorder; nervous system; drug screening /evaluation; Mammalia; Primates; behavioral /social science research tag;

substance abuse related disorder; nervous system; drug screening /evaluation; Primates; Mammalia; biological products; behavioral /social science research tag;

DESCRIPTION: Relapse is one of the most serious challenges facing successful treatment of cocaine addiction. Although the neurobiological basis of relapse is still poorly understood, growing evidence points to incidental re-exposure to cocaine (drug priming), environmental stimuli associated with previous cocaine use (drug cues), and stressful life events as key factors triggering craving and relapse in people. A comprehensive understanding of these relapse triggers is likely to lead to more effective treatment strategies. Research proposed in this application will make use of a novel nonhuman primate model developed during the previous project period to investigate neurobiological mechanisms underlying relapse to cocaine-seeking behavior. Specific Aim 1 will use selective dopamine receptor agonist and antagonists in conjunction with quantitative analytical techniques (pA2, isobolographic analysis) to delineate the roles of D1-like and D2-like receptor mechanisms in relapse to cocaine-seeking behavior. These studies will determine the degree and specificity with which selective D 1/5, D2, D3 and D4 receptor ligands mimic and/or modulate the reinstatement of drug seeking induced by cocaine priming and a cocaine-paired stimulus. Specific Aim 2 will use a complementary strategy to investigate the role of other monoaminergic (NE, 5-HT) as well as glutamatergic (NMDA, AMPA) mechanisms in relapse cocaine-seeking behavior. Specific Aim 3 will build on recent findings to develop a nonhuman primate model of relapse induced by social stress, to determine the relationship between behavioral and physiological markers of stress and relapse to cocaine-seeking behavior, and to investigate the role of corticotropin-releasing factor (CRF) and the hypothalamic-pituitary-adrenal (HPA) axis in stress-induced relapse. Overall, the proposed research will provide fundamental information about the neurobiological basis of relapse to cocaine-seeking behavior and will facilitate development of effective strategies for relapse prevention.

substance abuse related disorder; nervous system; drug screening /evaluation; Primates; Mammalia; biological products; behavioral /social science research tag;

substance abuse related disorder; nervous system; drug screening /evaluation; Primates; Mammalia; biological products; behavioral /social science research tag;

substance abuse related disorder; nervous system; model design /development; biological products; Mammalia; Primates; drug screening /evaluation; behavioral /social science research tag;

respiratory system; nervous system; drug screening /evaluation; cardiovascular system; biological products; Primates; Mammalia;

The D2 family of dopamine (DA) receptors is known to play an important role in the psychostimulant effects of cocaine. Less is known, however, about the contribution of different receptor subtypes (D2, D3, D4) within this family. In the present study, DA agonists differing in affinity and selectivity at the D3 receptor subtype were compared with reference D2 agonists for effects on schedule-controlled behavior in squirrel monkeys. Monkeys were trained to respond under a fixed-interval schedule of stimulus-shock termination shown previously to be sensitive to the stimulant effects of traditional D2 agonists as well as indirect DA agonists such as cocaine and amphetamine. In the majority of monkeys tested, the preferential D3 agonists PD 128,907, R-(+)-7-OH-DPAT, quinelorane, and quinpirole produced dose-related increases in response rate, with maximal effects comparable to those produced by the reference D2 agonists R-(-)-NPA and N-0434. The relative potencies of the D3 agonists for increasing response rate approximated their relative potencies reported in functional (stimulation of [3H]thymidine incorporation) and, to a lesser extent, radioligand binding assays (inhibition of [125I]iodosulpiride binding) in transfected cells expressing hD3 receptors. In contrast, the relative potencies of the reference D2 agonists [R-(-)-NPA about 40 times more potent than N-0434 approximated the relative potencies of these drugs reported in [125I]iodosulpiride binding assays in transfected cells expressing hD2, but not hD3, receptors. The results suggest a role for both the D2 and D3 receptor subtypes in mediating the stimulant effects of DA agonists and suggest that these mechanisms also may contribute to the effects of cocaine.

There is growing evidence for a modulatory role of serotonergic (5-HT) mechanisms in the abuse-related effects of cocaine in animals and humans. Our previous research showed that pharmacological inhibition of 5-HT uptake results in a dose-dependent attenuation of the discriminative stimulus (DS) effects of cocaine in monkeys, consistent with recent findings that 5-HT uptake inhibitors (e.g. Prozac ) can attenuate the subjective effects of cocaine in people. Less is known, however, about the role of different 5-HT receptor subtypes in mediating the cocaine-modulating effects of 5-HT. To address this issue, we have investigated the effects of receptor subtype-selective 5-HT agonists and antagonists in monkeys trained to discriminate cocaine from vehicle using procedures similar to those of our initial experiments. Among the drugs evaluated were the 5-HT1A agonists 8-OH-DPAT and buspirone, the 5-HT1B/2C agonist mCPP, the 5-HT2C agonist TFMPP, the nonselective 5-HT agonist quipazine, the 5-HT1A antagonist NAN 190, and the 5-HT2A/2C antagonist ritanserin. Each compound was studied first for its capacity to reproduce the DS effects of cocaine and, as warranted, to modify cocaine's DS effects when administered as a pretreatment. Of the compounds tested, only quipazine engendered consistent increases in cocaine-appropriate responding. Although full substitution for cocaine was typically not observed, quipazine engendered at least partial substitution in all monkeys. Additionally, the cocaine-like effects of quipazine (but not the effects of cocaine itself) were antagonized by ritanserin, and quipazine enhanced the DS effects of cocaine in an additive fashion. Pretreatment with other 5-HT receptor agonists or antagonists, however, did not produce consistent changes in the cocaine dose-response function regardless of dose. Although our findings support the prevailing view that 5-HT mechanisms play a modulatory role in the behavioral effects of cocaine, the relatively modest effects seen with most of the 5-HT compounds provide only limited encouragement for the development of these drugs as pharmacotherapies for cocaine abuse.

DESCRIPTION: (Applicant's Abstract) A growing number of polydrug abusers self-administer cocaine and heroin together, a combination commonly referred to as a "speedball". It has been reported that speedball abusers are more likely to fail in treatment, exhibit more severe psychopathology, and are at higher risk for contracting AIDS than either cocaine or heroin abusers. Despite the prevalence and detrimental consequences of speedball abuse, relatively little is known about its pharmacological basis or treatment. Recent studies have found enhanced effects of cocaine-opioid combinations compared to the effects of the individual drugs in both humans and nonhuman primates. Our proposed research will use established and novel primate models of drug abuse to identify pharmacological mechanisms underlying the enhanced effects of speedball mixtures and to evaluate candidate pharmacotherapies for speedball abuse. In rhesus monkeys trained to discriminate i.v. injections of either heroin or cocaine from vehicle, we will quantify the degree to which the effects of speedball combinations are enhanced compared to those of cocaine or heroin alone, determine the contribution of m and d-opioid and D1 and D2 dopamine receptor mechanisms using selective agonists and antagonists as pharmacological probes, and evaluate candidate pharmacotherapies that modulate the effects of both cocaine and heroin, and thus may interact uniquely with speedball mixtures. In monkeys trained to self-administer either heroin or cocaine under a progressive-ratio schedule of i.v. drug injection, we will use a conceptually similar approach to determine the extent to which the reinforcing potency and effectiveness of speedball combinations are enhanced compared to the individual drugs, characterize opioid and dopamine mechanisms in speedball self-administration, and evaluate candidate medications to reduce speedball abuse. Finally, using a novel primate model of drug relapse, we will determine the degree to which reinstatement of extinguished heroin-seeking or cocaine-seeking behavior is modified by speedball combinations, characterize opioid and dopamine receptor mechanisms in the relapse-inducing effects of speedballs, and evaluate candidate medications for relapse prevention. Overall, the proposed research will provide fundamental information about the pharmacological basis for and potential treatment of speedball addiction.

The overall objective of this program is to identify candidate medications that may function as pharmacological replacements for abused stimulants Synthetic efforts, conducted by H M Deutsch, Ph D , Georgia Institute of Technology, focus on derivitization of two indirect dopamine agonists, methylphenidate and the novel bicyclooctane LR-5182 The aim is to modify the structures of these compounds to generate potent, long-lasting drugs that substitute for cocaine and may thus prevent craving and withdrawal symptoms induced by drug abstinence (analogous to methadone for the treatment of heroin abuse) During the last project period we evaluated several structural derivatives of methylphenidate for their capacity of mimic the discriminative stimulus effects of cocaine in a manner predictive of cocaine-like subjective effects Monkeys were trained to discriminate a behaviorally active dose of cocaine (0 3 mg/kg, i m ) from vehicle using a two-choice drug discrimin ation pro cedure Under test conditions, cocaine, methylphenidate and a number of N-substituted and aromatic ring-substituted derivatives of methylphenidate induced dose-related increases in drug-appropriate responding reaching r 90% responses on the cocaine-associated lever Of these compounds dichloromethylphenidate, dichlororitalinol and dichlororitalinol methyl ester were more potent and had slower onsets and longer durations of action compared either cocaine or methylphenidate, suggesting that they may be suitable candidates for further evaluation in drug self-administration studies scheduled for the forthcoming year

Attention deficit hyperactive disorder (ADHD) is a complex developmental disorder with underlying emotional, attentional and learning disabilities Primary pharmacotherapies for ADHD are central nervous system stimulants, which indirectly enhance monoaminergic (especially dopaminergic) neurotransmission The current therapies provide symptomatic relief, but have restrictive side-effects, including abuse liability Growing anatomical and neurophysiological evidence suggests that histamine H3 receptors may play a modulatory role in monoaminergic transmission and arousal, implying that these receptors could constitute novel targets for the control of ADHD Recent studies suggest that the novel H3 antagonist GT-2331 has beneficial effects in rodent models predictive of anti-ADHD efficacy During the last project period we have evaluated GT-2331 for abuse potential in squirrel monkeys with a history of i v self-administration of cocaine Monkeys initially were tra ined to se lf-administer cocaine (0 1 mg/kg/injection, i v ) on a 30-response fixed-ratio schedule of reinforcement Once robust self-administration of cocaine was maintained consistently from day-to-day, saline was substituted for cocaine until self-administration was no longer maintained Subsequently, self-administration of a 10-fold range of doses of GT 2331 was evaluated Each dose, as well as vehicle, was tested for a minimum of three consecutive sessions and until no consistent trends in response rate were observed from day-to-day Over the range of doses tested, GT-2331 did not maintain self-administration behavior at levels consistently above those maintained by vehicle To the degree that these results can be generalized to people, our findings suggest that the use of GT-2331 for the treatment of ADHD may not be associated with significant abuse liability

DESCRIPTION (provided by applicant): The dual abuse of cocaine and heroin (commonly called "speedballs") is a pernicious form of drug addiction that has increased worldwide along with the increased availability of cocaine and heroin. Speedball abusers show a higher rate of failure in treatment, a greater incidence of psychopathology, and increased risk of HIV infection compared to abusers of the individual drugs. Despite the prevalence and detrimental consequences of speedball abuse, comparatively little is known about its neuropharmacological basis or treatment. Our previous research using nonhuman primate models of the subjective and reinforcing effects of drugs has revealed a distinctive pattern of interactions between cocaine and heroin, which appears to be mediated via mu and delta opioid and D1-like and D2-like dopamine receptor mechanisms. Our proposed research will build on these findings by investigating the role of specific receptor subtypes within these receptor families. In rhesus monkeys trained to discriminate IV cocaine from vehicle or to self-administer IV cocaine under a modified progressive-ratio schedule, we will use selective agonists and antagonists to investigate the contribution of subtypes of mu and delta receptors in heroin-induced enhancement of the discriminative stimulus and reinforcing effects of cocaine. In rhesus monkeys trained to discriminate IV heroin from vehicle or to self-administer IV heroin under a modified progressive-ratio schedule, we will use a similar strategy to investigate the contribution of D1-like and subtypes of D2-like receptors in cocaine-induced attenuation of the discriminative stimulus effects of heroin and cocaine-induced enhancement of the reinforcing effects of heroin. Quantitative pharmacological analyses, including in vivo apparent pA2 and isobolographic analysis, along with a novel behavioral economic model termed labor-supply will provide an objective framework for interpretation of drug interactions. The results of our proposed research will provide needed information about neuropharmacological mechanisms underlying speedball addiction and potential targets for medication development.

DESCRIPTION (provided by applicant): Alcoholism is a worldwide public health problem that is associated with debilitating medical, social, and psychological consequences. Alcoholism is characterized by persistent alcohol self-administration that is refractory to conventional interventions and by high vulnerability to relapse even after successful detoxification and abstinence. No broadly effective medications have been identified to combat alcohol abuse or relapse. Thus, the development of pharmacotherapies that reduce alcohol consumption and/or eliminate craving for alcohol remains a formidable challenge for the treatment of alcohol addiction. The purpose of this R21 proposal (RFA-AA-02-004) is to explore the role of GABAA/alpha5 receptor mechanisms in the behavioral effects of alcohol in nonhuman primates and to evaluate promising GABAA/alpha5 ligands as novel pharmacotherapies to treat alcohol addiction. Recent findings support a role for GABAA/alpha5 receptor mechanisms in alcohol's discriminative stimulus effects in monkeys and its reinforcing effects in rodents. In the proposed studies, the capacity of GABAA/alpha5 ligands to reduce oral self-administration of alcohol in rhesus monkeys will be investigated. In order to gauge the pharmacological specificity of these effects, GABAA/alpha5 ligands will also be evaluated in monkeys that self-administer sucrose solution instead of alcohol. In addition, concurrent observational studies will assess the degree to which GABAA/alpha5 ligands engender sedative and/or motoric side effects. Finally, in monkeys whose drug-seeking behavior has been extinguished and subsequently reinstated by alcohol priming, GABAA/alpha5 ligands will be evaluated for their ability to inhibit relapse to alcohol-seeking behavior. The ability of selected GABAA/alpha5 ligands to reduce oral alcohol self-administration and priming-induced reinstatement of alcohol seeking at doses that do not produce a generalized disruption of behavior or debilitating side effects may be predictive of potential therapeutic utility. The proposed studies will provide fundamental information regarding the viability of GABAA/alpha5 receptors as pharmacological targets for novel medications to reduce alcohol abuse and relapse.

neurotransmitter antagonist; cocaine; glutamate receptor; food; Primates; animal colony; self medication; appetite; behavioral /social science research tag;

substance abuse related behavior; craving; cocaine; antiadrenergic agents; animal colony; Primates; alpha adrenergic receptor; behavioral /social science research tag;

pharmacokinetics; Primates; animal colony; naltrexone;

cocaine; stimulant /agonist; Primates; animal colony;

substance abuse related behavior; cocaine; dopamine receptor; ligands; animal colony; Primates; suppression; behavioral /social science research tag;

substance abuse related behavior; craving; cocaine; Primates; animal colony; self medication; behavioral /social science research tag;

GABA receptor; Primates; animal colony; ethanol;

[unreadable] DESCRIPTION (provided by applicant): Glutamate is believed to play an integral role in the behavioral effects of cocaine related to its abuse. Most previous research has focused on the contribution of ionotropic glutamate receptor (iGluR) mechanisms, but growing evidence suggests that metabotropic glutamate receptors (mGluRs) may play an unexpectedly important role. Recent studies from our laboratory and others have shown that pharmacological blockade or genetic deletion of the mGluR subtype 5 (mGluR5) can attenuate key behavioral effects of cocaine in mice and monkeys. Our proposed research will build on initial findings in squirrel monkeys with three specific aims. Specific Aim 1 will use IV drug discrimination techniques to investigate the impact of mGluR5 antagonists and related drugs on the discriminative stimulus effects of cocaine. The contribution of dopamine (DA) and iGluR mechanisms in mGluR5 modulation of the discriminative stimulus effects of cocaine will be evaluated in drug interaction studies with direct and indirect DA agonists and NMDA and AMPA/kainate receptor antagonists. Specific Aim 2 will investigate the effects of mGluR5 antagonists and related drugs on IV self-administration of cocaine under a second-order schedule of reinforcement. Parallel studies using a comparable schedule of food delivery will assess the selectivity with which drugs modulate the reinforcing effects of cocaine without producing a generalized suppression of operant behavior. Observational studies will monitor potential side effects of drugs that selectively attenuate cocaine self-administration. Specific Aim 3 will use a reinstatement model of cocaine relapse to investigate the effects of mGluR5 antagonists and related drugs on cocaine-seeking behavior that has been extinguished and subsequently restored by cocaine priming and a cocaine-paired stimulus. The results will provide a needed empirical framework for evaluating mGluR5 and related glutamate receptor mechanisms in relevant nonhuman primate models of cocaine abuse and relapse. They should also provide new insights regarding mGluR5 as a potential target for the pharmacological management of cocaine addiction. [unreadable] [unreadable]

saliva; Saimiri; animal colony; cortisol;

DESCRIPTION (provided by applicant): Relapse is one of the most serious challenges facing long-term management of cocaine addiction. Clinical evidence points to initial re-exposure to cocaine (priming), stimuli associated with previous cocaine use, and stress as triggers of relapse in people. The same triggers induce reinstatement of cocaine seeking in laboratory animals, providing potentially useful models for investigating the biological basis of relapse. As a relatively nonselective inhibitor of dopamine (DAT), norepinephrine (NET), and serotonin transport (SERT), cocaine acts as an indirect agonist in all three monoamine systems. Compelling evidence supports a role for DA mechanisms in priming- and stimulus-induced reinstatement of cocaine seeking, and emerging data in nonhuman primates suggest that both NE and 5-HT mechanisms play significant modulatory roles. Inhibition of NET appears to be primarily facilitative with respect to reinstatement of cocaine seeking, whereas inhibition of SERT appears to be primarily inhibitory. Stress-induced reinstatement of drug seeking also appears to have a prominent NE component as well as a component mediated by central corticotropin releasing factor (CRF). Our proposed research will use nonhuman primate models developed previously under this grant to investigate the role of specific NE, 5-HT and CRF receptor subtypes in the reinstatement of drug seeking induced by a cocaine-paired stimulus alone and combined with cocaine priming and by pharmacological and ethologically-based stress. Specific Aim 1 will use selective NET inhibitors and selective NE agonists and antagonists to investigate the role of a1 and [unreadable] receptor mechanisms in the reinstatement of drug seeking following extinction of cocaine self-administration and after a comparable period of cocaine abstinence without explicit extinction of the operant response. Specific Aim 2 will use a conceptually similar strategy to investigate the role of a2 and CRF1 mechanisms in stress- induced reinstatement of cocaine seeking resulting from intruder confrontation and administration of yohimbine. Cross-over studies with those in Specific Aim 1 will determine the degree to which unique and overlapping mechanisms mediate priming- and stimulus-induced reinstatement of cocaine seeking compared to stress-induced reinstatement of cocaine seeking. Specific Aim 3 will use selective SERT inhibitors and selective agonists/antagonists to investigate the role of 5-HT1A and 5-HT2C mechanisms in 5-HT-mediated inhibition of reinstated cocaine seeking. Control studies involving reinstatement of food-seeking behavior and quantitative behavioral observations will determine the specificity with which drugs affect the reinstatement of cocaine seeking without inducing generalized disruptive effects. The proposed research will test specific hypotheses regarding NE, 5-HT and CRF mechanisms underlying reinstated cocaine seeking and provide pertinent information about potential pharmacological targets for the management of relapse.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project investigates at the molecular through behavioral levels the utility of dopamine D3 receptor antagonists and partial agonists for the treatment of substance abuse disorders.

8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo,exo))-; Abuse, Cocaine; Agonist; Aminoacetic Acid; Behavior; Behavior Therapy, Cognitive; Behavioral Therapy; CRISP; Cocaine; Cocaine Abuse; Cognitive Therapy; Complex; Computer Retrieval of Information on Scientific Projects Database; Cues; Development; Drug Therapy; Drugs; Extinction; Extinction (Psychology); Funding; Glutamate Receptor; Glycine; Grant; Institution; Investigators; Medication; NIH; National Institutes of Health; National Institutes of Health (U.S.); Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacotherapy; Psychotherapy, Cognitive; Research; Research Personnel; Research Resources; Researchers; Resources; Self Administration; Site; Source; Therapy, Cognition; United States National Institutes of Health; behavioral extinction; cognitive behavior intervention; cognitive behavior modification; cognitive behavioral intervention; cognitive behavioral modification; cognitive behavioral therapy; drug/agent; transport inhibitor

3,4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1,2-benzenediol; Abuse, Cocaine; Behavioral; CRISP; Cocaine Abuse; Computer Retrieval of Information on Scientific Projects Database; Dopamine; Economic Models; Funding; Grant; Hydroxytyramine; Institution; Investigators; Models, Economic; NIH; National Institutes of Health; National Institutes of Health (U.S.); Opiates; Opioid Receptor; Pharmacological Treatment; Receptor Protein; Receptors, Opiate; Research; Research Personnel; Research Resources; Researchers; Resources; Role; Source; United States National Institutes of Health; receptor; social role

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project investigates neuropharmacological mechanisms underlying the effects of kappa opioids in a nonhuman primate model of cocaine relapse. The research is designed to provide specific information on mechanisms of action and potential targets for development of medications to treat cocaine abuse.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Relapse is one of the most serious challenges facing long-term management of cocaine addiction. This project investigates monoaminergic receptor mechanisms underlying relapse to cocaine seeking and identifies potential pharmacological targets for the management of relapse.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project investigates the roles of specific opioid and dopamine receptor mechanisms in the dual abuse of cocaine and opioids to provide an objective framework for identifying receptor targets for the pharmacological management of speedball abuse.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project focuses on development of novel therapeutic approaches for treatment of Parkinson's disease.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project investigates the roles of specific opioid and dopamine receptor mechanisms in the dual abuse of cocaine and opioids to provide an objective framework for identifying receptor targets for the pharmacological management of speedball abuse.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This research investigates the ability of selective glycine site ligands and glycine transport inhibitors to accelerate extinction of cocaine-seeking behavior and deter relapse to cocaine self-administration. The approach serves as a translational interface for development of effective pharmacotherapies to augment extinction therapy for cocaine abuse.

DESCRIPTION (provided by applicant): The Research Training Program in Veterinary and Comparative Pathology at Harvard Medical School (HMS) is designed to prepare veterinarians for careers in biomedical research, with an emphasis on training in experimental pathology and in the use of nonhuman primate (NHP) models to study the pathogenesis and treatment of human diseases. This training grant is centered at the New England Primate Research Center (NEPRC) and includes the participation of other components of HMS and other area institutions. All trainees are at the postdoctoral level and are appointed as Research Fellows in the Department of Pathology of HMS. The training program is designed to follow a one year, NEPRC-funded period of intensive training in anatomical pathology. After appointment to the NCRR T32 program, trainees receive instruction in the design and implementation of experiments using NHP models, mentoring in the preparation of NIH grant applications and the peer review process, and broad exposure to state-of-the-art investigative tools and contemporary research methods used in experimental pathology, including immunohistochemistry, immunoelectron microscopy, in situ hybridization, flow cytometry, confocal microscopy, laser capture microdissection, PCR, and molecular biology. The training program will include formal coursework at HMS and the Harvard School of Public Health, participation in research conferences and seminars at the NEPRC, attendance at national and regional pathology and scientific meetings, and the completion of a research project under the supervision of an established investigator that results in the publication of manuscripts in peer-reviewed journals. Trainees pursuing a graduate degree may apply the research projects performed while supported by this training grant towards the fulfillment of the requirements of a PhD in graduate programs at Harvard University or the University of Massachusetts Medical School. Thus, this comprehensive training program will integrate the unique resources of the NEPRC, the outstanding research environment of Harvard Medical School and its affiliated institutions, and a field of established investigators to accomplish the long-term objective of providing qualified veterinarians with the requisite research training and experience to enable them to successfully compete for research funding as they prepare for academic careers as experimental pathologists and research scientists.

DESCRIPTION (provided by applicant): The Simian Immunodeficiency Virus (SlV)-infected Indian-origin rhesus monkey (Macaca mulatta) is the premiere animal model of human AIDS and has led to important advances in our understanding of disease pathogenesis, the role of viral determinants on disease progression, the impact of host immunity in controlling viral replication, and vaccine development. Rhesus macaques free of infection with Macacine herpesvirus 1 (B virus). Simian T lymphotropic Virus (STLV-1), Simian Retrovirus Type D (SRV-D), and SIV are essential to eliminate confounding variables associated with viral co-infections, to reduce the occupational health risks of working with macaques, and for overall colony health. The New England Primate Research Center (NEPRC) first established its specific-pathogen free (SPF) rhesus breeding colony in 1988, and the NEPRC SPF rhesus breeding colony is notable for its long history of i) high reproductive efficiency, ii) freedom from breaks in SPF status, iii) providing animals for AIDS-related investigations, and iv) cost-recovery. The goal of this application is to enhance the NEPRC SPF breeding colony production of well-characterized, SPF offspring for AIDS-related studies by optimizing colony management for maximum space utilization, maintaining high level reproductive efficiency, and improving behavioral management and environmental enrichment. Recently, with ARRA support, we have also MHC typed our entire SPF breeding colony using 454 sequencing providing important and unprecedented characterization for the MHC diversity of the breeding colony. The specific aims of this application are as follows: Specific Aim #1: Enhance and sustain the NEPRC rhesus macaque SPF breeding colony. Specific Aim #2: Continue MHC typing and genetic testing to provide for informed colony management and well-characterized animals for AIDS-related investigations.