Until the 1980s, it was generally believed that the actions of ethanol on biologic systems largely result from alterations in the fluidity of cell membranes, perhaps, with secondary effects on integral membrane proteins. This idea arose from the recognition that ethanol is a member of a group of anesthetic substances whose potency is related to their lipid solubility in accordance with the Meyer–Overton rule (22). More recently, it has been appreciated that some anesthetic actions are stereospecific and that direct protein interactions are likely (23). Indeed, ethanol modifies the functional activity of many receptors and ion channels, including NMDA (2425), kainate (26), serotonin 5-HT3 (27), GABAA (28), and glycine (29) receptors as well as G protein–coupled inwardly rectifying potassium channels (30) and calcium channels (31). In most cases, alcohol affects these targets only at high, suprapharmacologic concentrations. However, certain GABAA-receptor isoforms are exquisitely sensitive to alcohol so that functionally relevant effects can occur at concentrations within the intoxicating range (3233).
Since 1980, it has been known that alcohol can positively modulate the activity of some GABAA receptors (3435), but the importance of this finding was questioned because of inconsistency in the results from different laboratories and variability among brain regions. In addition, in experiments with recombinant GABAA receptors, low concentrations of GABA were not found to affect the most abundant GABAA-receptor isoforms, which contain the γ2 subunit. Recently, however, it has been discovered that GABAA receptors containing the δ subunit, in particular α4β2δ (36) and α6β2δ (37) receptors, are exceptionally sensitive to ethanol. Because δ subunit–containing GABAA receptors have a highly specific regional distribution, the lack of uniformity in the experimental results is now understandable. Indeed, brain regions that express δ subunits, including the cerebellum, cortical areas, thalamic relay nuclei, and brainstem (38), are among those that are recognized to mediate the intoxicating effects of alcohol. Mody (39) has proposed that such δ subunit–containing GABAA receptors are located largely perisynaptically or extrasynaptically, where they mediate tonic inhibition of neurons by ambient GABA. The functional role of tonic GABA current is still obscure (40), but the current could act to reduce network oscillations (41). It is interesting to speculate that extrasynaptic GABAA receptors may be activated by spillover of GABA when GABAergic interneurons are intensely activated, such as during a seizure discharge, thus producing negative feedback. Potentiation of extrasynaptic GABA receptors likely contributes to the anticonvulsant activity of ethanol, including its protective activity against alcohol withdrawal seizures.
Alcohol dependence—the existence of spontaneous behavioral disturbances that are produced by alcohol removal and suppressed by alcohol replacement—underlies the alcohol withdrawal syndrome. The mechanisms of alcohol dependence are less well understood than are those responsible for acute intoxication. However, it now appears that compensatory adaptation of GABAA receptors to prolonged ethanol exposure plays a critical role in alcohol dependence (42–44). Among the possible adaptive mechanisms, downregulation of GABAA receptors, as a result of decreases in the surface expression of α1 (45,46) or γ2 (47) subunits, is emerging as an important candidate. Indeed, prolonged ethanol exposure has been shown to increase the endocytic internalization of α1 subunit–containing receptors in clathrin-coated vesicles (48). The number of GABAA receptors in the postsynaptic density correlates directly with inhibitory synaptic strength. Thus, when alcohol is withdrawn and its potentiating effects are no longer present, the reduction in synaptic GABAA receptors is associated with impaired inhibitory tone, predisposing to withdrawal seizures. The mechanisms responsible for altered GABAA-receptor trafficking in response to prolonged alcohol exposure are not known. However, it has been proposed that enhancement of tonic GABA current could play a role (40).
In addition to decreases in α1- or γ2-subunit expression that occur with prolonged ethanol exposure, abrupt discontinuation of alcohol leads to a rapid increase in the abundance of α4 subunits (4749). Inhibitory synaptic currents mediated by GABAA receptors containing the α4 subunit exhibit markedly faster decay, leading to reduced charge transfer and decreased inhibitory function. Enhanced seizure susceptibility is observed in animals with increased α4-subunit expression (50,515051). Thus, alcohol withdrawal is associated with reduced density of synaptic GABAA receptors as well as alterations in GABAA-receptor subunit composition that lead to reduced inhibitory efficacy; both effects would be expected to predispose to seizures. Indeed, susceptibility to alcohol withdrawal seizures has been associated with a loss of GABA-mediated inhibition (5253).
Compensatory upregulation of NMDA and kainate receptors (54) as well as calcium channels (5556) also have been implicated in alcohol dependence and withdrawal seizures. For example, the inhibitory effects of ethanol on NMDA receptors (2425) leads to upregulation in the number of NMDA receptors in many brain regions, which may be an additional factor in the susceptibility to alcohol withdrawal seizures (5758). The relevance of this mechanism is highlighted by the fact that NMDA-receptor antagonists are highly effective anticonvulsants in animal models of alcohol withdrawal seizures (59).