Diverse effects of GABA-mimetic drugs on cocaine-evoked self-administration and discriminative stimulus effects in rats

Abstract

Recent data indicate that gamma-aminobutyric acid (GABA) is a modulator of behavioral responses to cocaine. The efficacy of gabapentin (a cyclic GABA analogue), tiagabine (a GABA reuptake inhibitor), or vigabatrin (an inhibitor of GABA transaminase and reuptake) to alter cocaine-seeking behavior and discriminative effects was examined in rats. Rats were trained to press a lever for cocaine (0.5 mg/kg per infusion) paired with a cue (light + tone) using a fixed ratio (FR) 5 schedule of reinforcement. After extinction, the cocaine-seeking behavior was reinstated by cocaine priming (10 mg/kg). Another group of rats was trained to discriminate cocaine (10 mg/kg) from saline in a two-lever FR 20 task. Vigabatrin (150-250 mg/kg) decreased cocaine-maintained responding, whereas tiagabine (10 mg/kg) significantly reduced responses on the "active" lever. Vigabatrin (150-250 mg/kg) significantly decreased responding to the cocaine-priming dose and a nonsignificant attenuation of cocaine-induced reinstatement was seen after tiagabine (5-10 mg/kg). Gabapentin (10-30 mg/kg) failed to alter maintenance of cocaine self-administration or drug-induced reinstatement. Pretreatment with either gabapentin, tiagabine, or vigabatrin resulted in neither reinstatement of cocaine seeking nor alterations in cocaine discrimination. Our study demonstrates that vigabatrin (only at the 150 mg/kg dose) exerted inhibitory actions on cocaine-maintained responding and attenuated the reinstatement of extinguishing responding more effectively than gabapentin or tiagabine and with less evidence of motor impairment than the latter drugs. Present findings do not support a role for gabapentin or tiagabine for the possible treatment of cocaine relapse, whereas albeit limited effects of vigabatrin may be seen.