Ethanol enhances α4β3δ and α6β3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans

gamma-Aminobutyric acid type A receptors (GABARs) have long been implicated in mediating ethanol (EtOH) actions, but so far most of the reported recombinant GABAR combinations have shown EtOH responses only at fairly high concentrations (greater than or equal to60 mM). We show that GABARs containing the delta-subunit, which are highly sensitive to gamma-aminobutyric acid, slowly inactivating, and thought to be located outside of synapses, are enhanced by EtOH at concentrations that are reached with moderate, social EtOH consumption. Reproducible ethanol enhancements occur at 3 mM, a concentration six times lower than the legal blood-alcohol intoxication (driving) limit in most states (0.08% wt/vol or 17.4 mM). GABARS responsive to these low EtOH concentrations require the GABAR delta-subunit, which is thought to be associated exclusively with alpha(4)- and a(6)-subunits in vivo, and the beta(3)-subunit, which has recently been shown to be essential for the in vivo anesthetic actions of etomidate and propofol. GABARs containing beta(2)- instead of beta(3)-subunits in alpha(4)betadelta- and alpha(6)betadelta-receptor combinations are almost 10 times less sensitive to EtOH, with threshold enhancement at 30 mM. GABARs containing gamma(2)- instead of delta-subunits with alpha(4)beta and alpha(6)beta are three times less sensitive to EtOH, with threshold responses at 100 mM, a concentration not usually reached with social EtOH consumption. These combined findings suggest that extrasynaptic delta-subunit-containing GABARs, but not their synaptic gamma-subunit-containing counterparts, are primary targets for EtOH.