The effects of continuous cocaine administration on GABA[subscript B] receptor functioning: behavioural and molecular studies

Abstract

The current experiments were aimed at understanding the association between GABA B receptors and withdrawal from continuous cocaine administration using behavioural and molecular techniques. In Experiment 1, the effects of baclofen, a GABA B receptor agonist, on basal and cocaine-induced locomotor activity were examined. Subjects were pretreated with cocaine (0, 5, 20 mg/kg/day) for 7 days and exposed to a 7-day withdrawal period. On day 7 of withdrawal, ambulation was measured in an open field for 60 min. In Experiment 1a, prior to testing, subjects were challenged with baclofen (0, 1.25, 2.5 mg/kg, i.p.). In Experiment 1b, subjects were challenged with the same doses of baclofen followed by a 15.0 mg/kg cocaine challenge 5 min later. The results indicated that cocaine administration reduced basal rearing and cocaine-induced hyperactivity. The 2.5 mg/kg baclofen challenge dose reduced basal and cocaine-induced locomotor activity in saline but not in cocaine pretreated animals. The 1.25 mg/kg baclofen dose attenuated cocaine-induced hyperactivity in saline pretreated animals. Low dose (1.25 mg/kg) baclofen abolished the effects of 5 mg/kg/day cocaine on rearing and sterotypies in response to cocaine challenge. In Experiment 2, the effects of continuous cocaine treatment on GABA B receptor protein levels were examined. Subjects were treated with continuous cocaine (0, 40 mg/kg/day) for a period of 3, 7 or 14 days and withdrawn from drug for 7 days. Following withdrawal, GABA B receptor protein levels in treated subjects were assessed by Western blot analysis. The data show that within the PFC and NACC, there were differences in GABA B receptor protein levels following 3 and 14 but not 7 days of cocaine pretreatment. Within the VTA, there were no differences in protein levels at any pretreatment period. The results of Experiments 1 & 2 suggest that the GABA B receptor system is involved in the effects of continuous cocaine and may influence actions at brain regions targeted in cocaine abuse.