This is a new R01 application designed to evaluate clinically relevant determinants of the remarkably sustained and selective effects of monoamine releasers on cocaine self-administration in rhesus monkeys. Cocaine abuse remains a major drug abuse problem, and the development of effective pharmacotherapies continues to be a high priority for NIDA. In preliminary studies, we have found that chronic treatment with modest doses of the monoamine releasers amphetamine and PHENMETRAZINE produced robust and selective reductions in cocaine- vs. food-maintained responding for up to 28 days in rhesus monkeys. Key elements of our results from monkeys have been demonstrated by others in human laboratory studies and clinical trials. We believe these findings support the proposition that monoamine releasers warrant further study as candidate agonist medications for cocaine dependence. Toward that end, this application proposes two Specific Aims to evaluate contextual and pharmacologic determinants of monoamine releaser effects.
Specific Aim 1 will examine effects of environmental and drug-history contexts on phenmetrazine-induced reductions in cocaine self-administration.
Specific Aim 1 a will evaluate phenmetrazine effects under conditions of alternative reinforcer availability. In clinical drug abuse treatment, pharmacotherapies are increasingly used in conjunction with contingency management techniques that introduce and control availability of alternative reinforcers. We propose to model this dual use of pharmacotherapies and alternative reinforcers, and we hypothesize that alternative reinforcer availability will enhance phenmetrazine-induced suppression of cocaine self- administration.
Specific Aim 1 b will evaluate phenmetrazine effects under conditions of extended access to and withdrawal from cocaine. In other drug classes (e.g. opioids), extended access promotes increased drug consumption, the development of physical dependence, and heightened drug reinforcement during withdrawal. Moreover, opioid agonist medications are most effective under conditions of withdrawal. We hypothesize that extended access to and withdrawal from cocaine will similarly enhance the ability of phenmetrazine to reduce cocaine self-administration.
Specific Aim 2 will examine pharmacokinetic and pharmacodynamic determinants of monoamine releaser effects.
Specific Aim 2 a will correlate pharmacokinetic and behavioral effects of PHENDIMETRAZINE, a phenmetrazine prodrug and Schedule III stimulant. We hypothesize that phendimetrazine will retain phenmetrazine's ability to produce selective decreases in cocaine self- administration, but that phendimetrazine will have a slow onset of action that correlates with generation of the active phenmetrazine metabolite.
Specific Aim 2 b will evaluate a series of monoamine releasers that vary in selectivity to release dopamine and serotonin vs. norepinephrine. We hypothesize that releasers with reduced noradrenergic effects will display reduced abuse liability but retain an ability to produce selective reductions in cocaine self-administration.

Public Health Relevance

Cocaine abuse remains a major public health problem, and the development of effective pharmacotherapies continues to be a high priority for NIDA. This application proposes a series of preclinical studies to assess contextual and pharmacologic factors that may influence the utility of monoamine releasers as candidate agonist medications. These studies may contribute to both (a) more effective implementation of existing monoamine releasers as agonist medications, and (b) the development of safer medications with reduced abuse liability.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Human Development Research Subcommittee (NIDA)
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Acri, Jane
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Virginia Commonwealth University
Schools of Medicine
United States
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Negus, S Stevens; Banks, Matthew L (2018) Pharmacokinetic-Pharmacodynamic (PKPD) Analysis with Drug Discrimination. Curr Top Behav Neurosci 39:245-259
Negus, S Stevens; Banks, Matthew L (2018) Modulation of drug choice by extended drug access and withdrawal in rhesus monkeys: Implications for negative reinforcement as a driver of addiction and target for medications development. Pharmacol Biochem Behav 164:32-39
Cornelissen, Jeremy C; Obeng, Samuel; Rice, Kenner C et al. (2018) Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys. J Pharmacol Exp Ther 365:37-47
Banks, Matthew L; Snyder, Rodney W; Fennell, Timothy R et al. (2017) Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: Evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys. Pharmacol Biochem Behav 156:30-38
Thomsen, Morgane; Barrett, Andrew C; Butler, Paul et al. (2017) Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats. J Pharmacol Exp Ther 362:161-176
Lazenka, Matthew F; Negus, S Stevens (2017) Oral modafinil facilitates intracranial self-stimulation in rats: comparison with methylphenidate. Behav Pharmacol 28:318-322
Banks, Matthew L; Negus, S Stevens (2017) Insights from Preclinical Choice Models on Treating Drug Addiction. Trends Pharmacol Sci 38:181-194
Lazenka, M F; Suyama, J A; Bauer, C T et al. (2017) Sex differences in abuse-related neurochemical and behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA) in rats. Pharmacol Biochem Behav 152:52-60
Banks, Matthew L; Czoty, Paul W; Negus, Sidney S (2017) Utility of Nonhuman Primates in Substance Use Disorders Research. ILAR J 58:202-215
Moerke, Megan J; Banks, Matthew L; Cheng, Kejun et al. (2017) Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys. Drug Alcohol Depend 181:85-93

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