Abstract
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.
Footnotes
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This work was supported by Grants R01-DA02519, R01-DA12970, P01-DA14528, and K05-DA00101 from National Institute on Drug Abuse, National Institutes of Health (NIDA, NIH), and by the Intramural Research Program of NIDA, NIH.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.107383.
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ABBREVIATIONS: PAL-287, 1-naphthyl-2-propylamine hydrochloride; PAL-314, m-methylamphetamine, 1-(3-toluyl)-2-propylamine fumarate; and PAL-353, m-fluoroamphetamine, 1-(3-fluorophenyl)-2-propylamine fumarate; DA, dopamine; NE, norepinephrine; 5HT, 5-hydroxytryptaime (serotonin); FR, fixed ratio; VR, variable ratio.
- Received May 4, 2006.
- Accepted October 26, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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