Allopregnanolone and Pentobarbital Infused Into the Nucleus Accumbens Substitute for the Discriminative Stimulus Effects of Ethanol

Abstract

Background: The discriminative stimulus effects of ethanol are mediated in part by the γ‐aminobutyric acid type A (GABAA) receptor system. We have previously shown that microinjections of the competitive GABAA 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 GABAA 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 GABAA‐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 GABAA receptors in the nucleus accumbens produces full substitution for the stimulus effects of ethanol. This suggests that GABAA receptors in the nucleus accumbens may play a more influential role in the discriminative stimulus effects of ethanol than those in the hippocampus.