Received for publication May 5, 2006.
Revised October 26, 2006.
Accepted for publication October 26, 2006.

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

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 vs. serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that non-selective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine for the treatment of cocaine abuse. 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 (PAL-353, methamphetamine, PAL-314, PAL-287, fenfluramine). In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg, SC) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine vs. serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/inj) and food (1 gm pellets) under a second-order FR2(VR16: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 non-selective 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.

Key words: amphetamine, cocaine, drug discrimination, monoamine releaser, rhesus monkey, self-administration