Dopamine D2 and GABA(A) Receptors Differentially Regulate Ethanol-Induced Aversion and Reward Through Corticolimbic Circuits

Ethanol produces both aversive and rewarding effects during the intoxication phase; however, the receptor-specific pharmacological mechanisms and neural circuits underlying this paradox remain poorly defined. The present study investigated how dopamine D2 and GABA(A) receptor systems differentially regulate ethanol-induced aversion and reward at behavioral and neural circuit levels. Rats received systemic administration of the dopamine D2 receptor agonist apomorphine, the GABA(A) receptor agonist muscimol, or the GABA(A) receptor antagonist bicuculline prior to ethanol conditioning. Ethanol-induced aversion and reward were assessed using conditioned taste aversion (CTA) and conditioned place preference (CPP), respectively, and neural activation was examined using c-Fos immunohistochemistry in the medial prefrontal cortex, amygdala, and hippocampus. Apomorphine potentiated ethanol-induced CTA while suppressing ethanol-induced CPP. In contrast, bicuculline attenuated ethanol-induced CTA and abolished ethanol-induced CPP, whereas muscimol enhanced aversive CTA and converted ethanol-induced CPP into conditioned place aversion. During CTA, apomorphine predominantly changed c-Fos expression in amygdalar and hippocampal subregions, whereas GABA(A) receptor manipulation altered activity within the medial prefrontal–amygdala–hippocampal network. During CPP, dopamine D2 receptor activation enhanced neural activity in the medial prefrontal cortex and hippocampus while suppressing central amygdala activity, whereas GABA(A) receptor modulation reduced prefrontal activation and enhanced amygdalar and hippocampal engagement. Altogether, these findings reveal receptor-specific and context-dependent corticolimbic mechanisms through which dopamine D2 and GABA(A) receptors differentially regulate ethanol-induced aversive and rewarding states during acute intoxication.