Alcohol-sensitive GABA receptors and alcohol antagonists.

A lcohol is one of the oldest and most widely used and abused of all psychoactive drugs. Although alcohol ingestion impacts most organ systems, its effects on the brain are of considerable interest, given alcohol’s many neuropharmacological actions, including its intoxicating, sedative, anxiolytic, reinforcing, and addictive properties (1). However, elucidating the cellular and molecular targets for alcohol’s important pharmacological actions has proven challenging. Alcohol has a relatively simple chemical structure, it has pleiotropic effects in disordering membrane lipids and proteins, and relatively high clinically relevant (5–30 mM) tissue concentrations are required for its actions. Thus, it is unlikely that any single molecular mechanism (or target for that matter) will explain all of the relevant pharmacology of this important drug. Despite these caveats, research over the past two decades has identified a number of potential alcohol targets in brain, including various G protein-coupled receptors and ligand-gated ion channels (1). In some cases, alcohol has been shown to modify these targets at pharmacologically relevant concentrations; however, with few exceptions, the concentrations (or doses) of alcohol studied have been well above those that cause acute intoxication in animals, including humans. Despite considerable work in this area, two important questions remain largely unanswered. Can any of the clinically relevant neuropharmacological actions of alcohol be attributed to a direct interaction with one or more ‘‘specific’’ protein targets, such as a receptor or ion channel? If so, can the neuropharmacological actions of alcohol be mimicked, modified, or even blocked by a much more specific drug acting at this same target(s)? In this issue of PNAS, Hanchar et al. (2) and Wallner et al. (3) provide compelling data for a rather specific and pharmacologically relevant alcohol binding site on a subtype of GABAA receptor composed of 4 6 3 subunits. Remarkably, they show that the behavioral alcohol antagonist Ro15– 4513 binds to the same (or overlapping) site and competes with and antagonizes the actions of low to moderate concentrations of alcohol in potentiating GABAinduced Cl currents. Thus, the authors provide exciting new evidence for a highly specific interaction of alcohol with a subtype of GABAA receptor that may mediate (at least in part) some of this drug’s most important behavioral effects.