The role of GABA(A) receptors in the acute and chronic effects of ethanol.

ABSTRACT

GABA(A) receptors are sensitive to ethanol in distinct brain regions and are clearly involved in the acute actions of ethanol, ethanol tolerance, ethanol dependence and ethanol self-administration. Data from a variety of perspectives such as molecular, cellular and behavioral analysis have elucidated the role of GABA(A) receptors in these processes. GABA(A) receptor activation mediates many of the behavioral effects of ethanol including motor incoordination, anxiolysis and sedation. The actions of ethanol at GABA(A) receptors are influenced by endogenous modulators such as the neuroactive steroids. Sensitization to these compounds influences ethanol dependence and withdrawal and may explain gender differences in the molecular effects of ethanol. Furthermore, GABA(A) receptors may also play a role in ethanol self-administration via the mesolimbic reward system. Ethanol tolerance and dependence may be explained, in part, by changes in the function of GABA(A) receptors. We have proposed that alterations in native GABA(A) receptor subunit assembly could alter the functional properties of these receptors. However, post-translational modifications or other post-synaptic mechanisms may also explain changes in GABA(A) receptor function. Genetic animal models of ethanol dependence have also identified GABA(A) receptor genes as likely mediators of the behavioral adaptations associated with ethanol dependence and withdrawal. A better understanding of the effects of ethanol at GABA(A) receptors has highlighted important potential mechanisms involved in the development of alcoholism.