Effects of GABA(B) receptor antagonist, agonists and allosteric positive modulator on the cocaine-induced self-administration and drug discrimination

Abstract

Preclinical and clinical findings indicate that a GABA(B) receptor agonist baclofen decreases cocaine use. The present study investigated the effects of the GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), the agonists baclofen and 3-aminopropyl(methyl)phoshinic acid (SKF 97541) and the allosteric positive modulator 3,5-bis(1,1-dimethylethyl-4-hydroxy-beta,beta-dimethylbenzenepropanol (CGP 7930) in cocaine-and food-maintained responding under a fixed ratio 5 schedule of reinforcement in male Wistar rats. The effects of the GABA(B) receptor ligands on cocaine (10 mg/kg)-induced discriminative stimulus in a two-lever, water-reinforced fixed ratio 20 task and on basal locomotor activity were also assessed. Baclofen (2.5-5 mg/kg), SKF 97541 (0.1-0.3 mg/kg) and CGP 7930 (30-100 mg/kg) decreased the cocaine (0.5 mg/kg/injection)-maintained responding; SCH 50911 (3-10 mg/kg) was inactive in this respect. Baclofen (5 mg/kg) and SKF 97541 (0.3 mg/kg), but not CGP 7930 or SCH 50911 attenuated the food-maintained responding. The inhibitory effects of the GABA(B) receptor agonists and the modulator were blocked by SCH 50911. SKF 97541 (0.1 mg/kg) or CGP 9730 (30-100 mg/kg) did not produce a significant shift in the cocaine (1.25-10 mg/kg) dose-response curve in a drug discrimination procedure, while baclofen (1.5 mg/kg) or SCH 50911 (10 mg/kg) attenuated the effects of separate doses of cocaine. Baclofen (5 mg/kg) and CGP 7930 (100 mg/kg) significantly reduced basal horizontal activity. We found that pharmacological stimulation of GABA(B) receptors by direct agonists or allosteric positive modulation reduces cocaine reinforcement while this property of cocaine is not related to tonic activation of GABA(B) receptors. The GABA(B) receptor stimulation-induced reduction of cocaine reinforcement was separated from its discriminative stimulus effects. Moreover, a dissociation between effects of direct GABA(B) receptor agonists and a GABA(B) allosteric positive modulator on cocaine vs. food-maintained responding was demonstrated.