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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Bauer, Clayton T; Negus, S Stevens; Blough, Bruce E et al. (2016) Cocaine-like discriminative stimulus effects of phendimetrazine and phenmetrazine in rats. Behav Pharmacol 27:192-5
Solis Jr, Ernesto; Suyama, Julie A; Lazenka, Matthew F et al. (2016) Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters. Sci Rep 6:31385
Hutsell, Blake A; Negus, S Stevens; Banks, Matthew L (2016) Effects of 21-day d-amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys. Drug Alcohol Depend 168:36-44
Banks, Matthew L; Negus, S Stevens (2016) Insights from Preclinical Choice Models on Treating Drug Addiction. Trends Pharmacol Sci :
Lazenka, Matthew F; Legakis, Luke P; Negus, S Stevens (2016) Opposing effects of dopamine D1- and D2-like agonists on intracranial self-stimulation in male rats. Exp Clin Psychopharmacol 24:193-205
Lazenka, Matthew F; Blough, Bruce E; Negus, S Stevens (2016) Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats. J Sex Med 13:338-49
Hutsell, Blake A; Cheng, Kejun; Rice, Kenner C et al. (2016) Effects of the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) on cocaine versus food choice and extended-access cocaine intake in rhesus monkeys. Addict Biol 21:360-73
Schwienteck, Kathryn L; Negus, S Stevens; Poklis, Justin L et al. (2015) Effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in male rhesus monkeys. Exp Clin Psychopharmacol 23:395-404
Altarifi, Ahmad A; Yuan, Yunyun; Zhang, Yan et al. (2015) Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats. Psychopharmacology (Berl) 232:815-24
Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L et al. (2015) Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction. Curr Treat Options Psychiatry 2:136-150

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