Discriminative stimulus function of ethanol: Role of GABA(A) receptors in the nucleus accumbens

Because the subjective effects of drugs may be related to abuse potential, this study was conducted to assess the involvement of GABA, receptor systems in the nucleus accumbens (N Acc) in the discriminative stimulus effects of ethanol. Male Long-Evans rats were trained to discriminate between intraperitoneal (IP) injections of ethanol (1 g/kg) and saline under a fixed-ratio 10 schedule of sucrose (10% w/v) reinforcement. When performance during training sessions met the accuracy criteria (>80% correct responding for five consecutive days), an ethanol generalization curve was determined. The rats were then surgically implanted with bilateral stainless-steel guide cannulae aimed at the N Acc. Intra-accumbens (IA) substitution test sessions were conducted during which the direct GABA(A) agonist muscimol (0.01, 0.04, 0.10, and 0.40 mu g/mu l; IA) was administered in combination with saline (IP). The direct GABA(A) antagonist bicuculline (0.03, 0.10, and 0.30 mu g/mu l; IA) was administered in combination with the training dose of ethanol (1 g/kg, ip). At 10-min postinjection, IA muscimol partially substituted for IP ethanol. However, at 15-min postinjection, muscimol (0.10 mu g/mu l; IA) fully substituted for IP ethanol. Bicuculline attenuated the discriminative stimulus properties of IP ethanol, but only at doses that significantly decreased response rate. At 10-min postinjection, muscimol (0.01 and 0.04 mu g/mu l) potentiated (>80% ethanol lever responding) the discriminative stimulus properties of a dose of ethanol (0.5 g/kg) that alone produced only partial generalization. These data suggest that ethanol discrimination is mediated centrally and demonstrate that infusions of the GABA(A) agonist muscimol in the N Acc are sufficient to produce the stimulus effects corresponding to a 1.0 g/kg training dose of ethanol. When taken together with data showing that GABA(A) receptor activation in the N Acc potentiates the termination of ethanol self-administration, these data suggest that ethanol's discriminative stimulus function may influence its reinforcement function.