Based on the similarity of ethanol intoxication to the behavioral effects of drugs known to target GABAA receptors (GABARs) it has been suspected for decades that ethanol facilitates the activity of GABA. Even so, it has been surprisingly difficult to identify molecular targets of ethanol. Research conducted over the past several years suggests that a subclass of GABARs (those containing δ subunits) responds in a relevant concentration range to ethanol. Although δ subunit-containing GABARs are not ubiquitously expressed at inhibitory synapses like their γ subunit-containing, synaptic counterparts, they are found in many neurons in extrasynaptic locations. Here they give rise to a tonic form of inhibition that can potently suppress neuronal excitability. Studies have shown that both recombinant and native δ subunit-containing GABARs: 1) are modulated by behaviorally-relevant (i.e. low millimolar) concentrations of ethanol, 2) directly bind ethanol over the same concentration range, 3) show altered function upon single amino substitutions linked to changes in behavioral responsiveness to ethanol, and 4) are a site of action of Ro15-4513, a competitive antagonist of ethanol binding and a drug which prevents many of the behavioral aspects of ethanol intoxication. Despite such comprehensive evidence, however, the field is not free from controversy. This review evaluates published data for and against a central role of δ subunit-containing GABARs in ethanol actions and suggests future directions that might help settle points of controversy.
Keywords: alpha6 subunit, alpha4 subunit, delta subunit, alcohol, cerebellum, tonic inhibition