Discriminative Stimulus Function of Ethanol: Role of GABA, 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_A 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%0 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_Aagonist muscimol (0.01, 0.04, 0.10, and 0.40 μg/μl; IA) was administered in combination with saline (IP). The direct GABA_A, antagonist bicuculline (0.03,0.10, and 0.30 μg/μl; 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 μg/μl; 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 μg/μl) potentiated (>80%0 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.