Effects of the kappa-opioid receptor agonist, U69593, on the development of sensitization and on the maintenance of cocaine self-administration

Previous studies showed that prior administration of kappa-opioid agonists decreased the development of sensitization to some of the behavioral effect s of cocaine. The present study sought to determine whether the development of sensitization to cocaine's reinforcing effects was also sensitive to an tagonism by kappa-opioid agonists. During a pretreatment phase, the kappa-o pioid agonist, U69593 (0.0 ou 0.32 mg/kg) was administered prior to (1) 2 d aily injections of cocaine (0.0 or 20.0 mg/kg), or (2) cocaine or saline ad ministered via a yoking procedure. Cocaine pretreatment decreased the laten cy to acquisition of cocaine self-administration. However, prior administra tion of U69593 during the pretreatment phase failed to attenuate the develo pment of this sensitized response to cocaine's reinforcing effect. In other groups, the effect of acute U69593 pretreatment on the maintenance of coca ine self-administration was examined during a 10 hr session. During trainin g and testing, a stimulus was associated with each self-administered cocain e infusion for one group whereas responding of another group was reinforced by a cocaine infusion alone. On the test day, pretreatment with U69593 (0. 32 mg/kg) decreased responding during each hour of the 10 hr session for th e group that was reinforced with cocaine plus the cocaine-associated stimul us. U69593 failed to produce a long-lasting disruption of cocaine self-admi nistration for vats that were trained and tested without the cocaine-associ ated stimulus. These data suggest that the acquisition and maintenance of c ocaine self-administration ave differentially sensitive to manipulations of kappa-opioid systems. Futher, the disruption of cocaine selfadministration by U69593 may be due to interactions with mechanisms that underlie facilit ative effects of stimuli that have been associated with self-administered c ocaine infusions. (C) 2001 American College of Neuropsychopharmacology. Pub lished by Elsevier Science Inc.