The GABAB agonist baclofen modifies cocaine self-administration in rats

Abstract

The present experiments were conducted to examine further the ability of GABAergic compounds to modify the reinforcing effects of cocaine. In male Sprague-Dawley rats, behaviour was maintained under a fixed-ratio (FR)-5 with a 240 s timeout (TO) multiple schedule of cocaine (0.66 mg/kg/infusion) and food (45 mg) in 180 min sessions. Once rats could reliably nose-poke for comparable number of reinforcers over sessions, and demonstrate extinction selectively for each reinforcer, pretreatments were examined. The GABAB agonist baclofen (2.5-10.0 mg/kg i.p.) administered 30 min before the start of the session, dose-dependently attenuated behaviour maintained by cocaine, whereas responding maintained by food was marginally decreased. 4,5,6,7-Tetrahydroisoxazolo [5,4-c]pyridin-3-ol hydrochloride (THIP) (2-8 mg/kg i.p.) a GABAA agonist failed to modify cocaine-maintained or food-maintained responding. In another experiment, behaviour maintained by cocaine (0.66 mg/kg/infusion) under an FR-5 TO 20 s schedule of reinforcement was attenuated by intra-nucleus accumbens (100-300 ng) or intra-ventral tegmental area (300 ng) administration of baclofen. Similar doses of baclofen administered into the striatum had no effect. Repeated systemic pretreatment for 3 days with baclofen (2.5 mg/kg i.p.) produced gradual decreases in cocaine-maintained responding. A larger dose (5.0 mg/kg i.p.) tested repeatedly for 5 days decreased the number of cocaine injections self-administered. The present findings demonstrate that modulation of GABA systems may have therapeutic potential for the treatment of psychomotor stimulant abuse.