Allopregnanolone and pentobarbital infused into the nucleus accumbens substitute for the discriminative stimulus effects of ethanol

Background: The discriminative stimulus effects of ethanol are mediated in part by the γ-aminobutyric acid type A (GABA_A) receptor system. We have previously shown that microinjections of the competitive GABA_A agonist muscimol in the nucleus accumbens and amygdala fully substitute for the discriminative stimulus effects of systemic ethanol. However, it is not known whether allosteric binding sites on GABA_A receptors located within specific limbic brain regions contribute to the discriminative stimulus effects of ethanol. Methods: Male Long-Evans rats were trained to discriminate between intraperitoneal injections of ethanol (1 g/kg) and saline under a fixed-ratio 10 schedule of sucrose (10% w/v) reinforcement. Injector guide cannulae, aimed at both the nucleus accumbens core and the hippocampus area CA1, were then implanted to allow site-specific infusion of GABA_A-positive modulators. Results: Infusion of the neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone, or 3α-5α-P) in the nucleus accumbens resulted in dose-dependent full substitution for intraperitoneal ethanol (50% effective dose = 0.38 ng/μl per side). Likewise, injection of the barbiturate pentobarbital into the nucleus accumbens also substituted dose-dependently for ethanol (50% effective dose = 1.55 μg/μl per side). However, infusions of either 3α-5α-P or pentobarbital in the hippocampus failed to substitute for ethanol and produced inverted U-shaped dose-response curves. Conclusions: These results demonstrate that allosteric positive modulation of GABA_A receptors in the nucleus accumbens produces full substitution for the stimulus effects of ethanol. This suggests that GABA_A receptors in the nucleus accumbens may play a more influential role in the discriminative stimulus effects of ethanol than those in the hippocampus.