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 gamma -aminobutyric acid type A (GABA(A)) receptor system. We h ave previously shown that microinjections of the competitive GABA(A) agonis t muscimol in the nucleus accumbens and amygdala fully substitute for the d iscriminative stimulus effects of systemic ethanol. However, it is not know n whether allosteric binding sites on GABA(A) receptors located within spec ific limbic brain regions contribute to the discriminative stimulus effects of ethanol. Methods: Male Long-Evans rats were trained to discriminate between intraper itoneal injections of ethanol (1 g/kg) and saline under a fixed-ratio 10 sc hedule of sucrose (10% w/v) reinforcement. Injector guide cannulae, aimed a t both the nucleus accumbens core and the hippocampus area CA1, were then i mplanted to allow site-specific infusion of GABA(A)-positive modulators. Results: Infusion of the neurosteroid 3 alpha -hydroxy-5 alpha -pregnan-20- one (allopregnanolone, or 3 alpha -5 alpha -P) in the nucleus accumbens res ulted in dose-dependent full substitution for intraperitoneal ethanol (50% effective dose = 0.38 ng/mul per side). Likewise, injection of the barbitur ate pentobarbital into the nucleus accumbens also substituted dose-dependen tly for ethanol (50% effective dose = 1.55 mug/mul per side). However, infu sions of either 3 alpha -5 alpha -P or pentobarbital in the hippocampus fai led 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 fo r the stimulus effects of ethanol. This suggests that GABA(A) receptors in the nucleus accumbens may play a more influential role in the discriminativ e stimulus effects of ethanol than those in the hippocampus.