GABAA Receptor Subtype Mechanisms and the Abuse-Related Effects of Ethanol: Genetic and Pharmacological Evidence

Abstract

Ethanol’s reinforcing and subjective effects, as well as its ability to induce relapse, are powerful factors contributing to its widespread use and abuse. A significant mediator of these behavioral effects is the GABAA receptor system. GABAA receptors are the target for γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. Structurally, they are pentameric, transmembrane chloride ion channels comprised of subunits from at least eight different families of distinct proteins. The contribution of different GABAA subunits to ethanol’s diverse abuse-related effects is not clear and remains an area of research focus. This chapter details the clinical and preclinical findings supporting roles for different α, β, γ, and δ subunit-containing GABAA receptors in ethanol’s reinforcing, subjective/discriminative stimulus, and relapse-inducing effects. The reinforcing properties of ethanol have been studied the most systematically, and convergent preclinical evidence suggests a key role for the α5 subunit in those effects. Regarding ethanol’s subjective/discriminative stimulus effects, clinical and genetic findings support a primary role for the α2 subunit, whereas preclinical evidence implicates the α5 subunit. At present, too few studies investigating ethanol relapse exist to make any solid conclusions regarding the role of specific GABAA subunits in this abuse-related effect.