EVALUATION OF THE REINFORCING AND DISCRIMINATIVE STIMULUS EFFECTS OF COCAINE IN COMBINATION WITH (-AJ-76 OR CLOZAPINE())

Because self-administration and discrimination of a drug by animals co rrelate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of th e drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autorece ptor antagonist (+)-AJ 76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocai ne in monkeys. One group of rhesus monkeys (n = 6) was allowed to self -administer cocaine (0.03 or 0.1 mg/kg/injection i.v., fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discrimin ate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behav ior was stable, AJ or CLZ was administered i.m., 15 or 30 min presessi on. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ de creased cocaine self-administration in an apparently nonspecific manne r. When combined with saline, partial substitution for cocaine was see n in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, b oth AJ and CLZ decreased drug appropriate responding by at least 50% i n two of four monkeys, but had little or no effect in the other monkey s up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest th at any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stim ulant effects of AJ observed in rats were not prominent in monkeys.