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BEHAVIORAL PHARMACOLOGY

Monoamine Releasers with Varying Selectivity for Dopamine/Norepinephrine versus Serotonin Release as Candidate "Agonist" Medications for Cocaine Dependence: Studies in Assays of Cocaine Discrimination and Cocaine Self-Administration in Rhesus Monkeys

Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, Massachusetts (S.S.N., N.K.M.); Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina (B.E.B.); and Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (M.H.B., R.B.R.)

Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.

Address correspondence to: Dr. S. Stevens Negus, Alcohol and Drug Abuse Research Center, McLean Hospital; Harvard Medical School, 115 Mill St., Belmont, MA 02478-9106. E-mail: negus{at}mclean.harvard.edu

This article has been cited by other articles:

				S. S. Negus, M. H. Baumann, R. B. Rothman, N. K. Mello, and B. E. Blough Selective Suppression of Cocaine- versus Food-Maintained Responding by Monoamine Releasers in Rhesus Monkeys: Benzylpiperazine, (+)Phenmetrazine, and 4-Benzylpiperidine J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 272 - 281. [Abstract] [Full Text] [PDF]