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)
Project #
Application #
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Acri, Jane
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Schools of Medicine
United States
Zip Code
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
Bull, Cecilia; Freitas, Kelen C C; Zou, Shiping et al. (2014) Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence. Neuropsychopharmacology 39:2835-45
Banks, Matthew L; Bauer, Clayton T; Blough, Bruce E et al. (2014) Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys. Exp Clin Psychopharmacol 22:274-84
Howell, Leonard L; Negus, S Stevens (2014) Monoamine transporter inhibitors and substrates as treatments for stimulant abuse. Adv Pharmacol 69:129-76
Bonano, Julie S; Runyon, Scott P; Hassler, Carla et al. (2014) Effects of the neuropeptide S receptor antagonist RTI-118 on abuse-related facilitation of intracranial self-stimulation produced by cocaine and methylenedioxypyrovalerone (MDPV) in rats. Eur J Pharmacol 743:98-105
Banks, Matthew L (2014) Effects of the nicotinic acetylcholine receptor antagonist mecamylamine on the discriminative stimulus effects of cocaine in male rhesus monkeys. Exp Clin Psychopharmacol 22:266-73
Nader, Michael A; Banks, Matthew L (2014) Environmental modulation of drug taking: Nonhuman primate models of cocaine abuse and PET neuroimaging. Neuropharmacology 76 Pt B:510-7
Bonano, J S; Glennon, R A; De Felice, L J et al. (2014) Abuse-related and abuse-limiting effects of methcathinone and the synthetic "bath salts" cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats. Psychopharmacology (Berl) 231:199-207
Negus, S Stevens; Miller, Laurence L (2014) Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 66:869-917
Bauer, Clayton T; Banks, Matthew L; Negus, S Stevens (2014) The effect of chronic amphetamine treatment on cocaine-induced facilitation of intracranial self-stimulation in rats. Psychopharmacology (Berl) 231:2461-70

Showing the most recent 10 out of 19 publications