GABA_A receptor modulation of the rewarding and aversive effects of ethanol

Ethanol has been shown to exert many of its biochemical and behavioral effects through an interaction with the gamma-aminobutyric acid (GABA) receptor system. This review focuses on a subset of studies that has used self-administration, as well as place and taste conditioning, procedures to investigate a role for the GABA_A receptor system in modulating the rewarding and aversive effects of ethanol. Potential advantages and disadvantages of each procedure are also discussed. A significant amount of evidence supports the suggestion that GABA_A receptors are important modulators of the motivational effects of ethanol, although most of the findings have been obtained from studies examining oral ethanol self-administration. Relatively fewer studies have investigated ethanol place and taste conditioning. All self-administration studies reviewed used rats, whereas most conditioning studies used mice. Results of these studies show that GABA_A antagonists and inverse agonists reduce ethanol self-administration under limited-access conditions. The effect of GABA_A agonists on ethanol self-administration is less clear due to their bidirectional effects. GABA_A receptor antagonists have been shown to increase ethanol-induced conditioned place preference and conditioned taste aversion in mice and decrease ethanol-induced conditioned taste aversion in rats. Issues related to interpretation and integration of these findings across models and species are considered. The integration of data from self-administration and conditioning procedures is necessary to define the role of GABA_A receptors in modulating the rewarding and aversive effects of ethanol and may lead to the development of pharmacotherapies that target GABA_A receptors to treat alcoholism in human beings.