Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition

Based on the similarity of ethanol intoxication to the behavioral effects of drugs known to target gamma-aminobutyric acid type A (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 delta subunits) responds in a relevant concentration range to ethanol. Although delta subunit-containing GABARs are not ubiquitously expressed at inhibitory synapses like their gamma 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 delta 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 delta subunit-containing GABARs in ethanol actions and suggests future directions that might help settle points of controversy.