GABA.sub.A Receptors Containing [rho]1 Subunits Contribute to In Vivo Effects of Ethanol in Mice

GABA.sub.A receptors consisting of [rho]1, [rho]2, or [rho]3 subunits in homo- or hetero-pentamers have been studied mainly in retina but are detected in many brain regions. Receptors formed from [rho]1 are inhibited by low ethanol concentrations, and family-based association analyses have linked [rho] subunit genes with alcohol dependence. We determined if genetic deletion of [rho]1 in mice altered in vivo ethanol effects. Null mutant male mice showed reduced ethanol consumption and preference in a two-bottle choice test with no differences in preference for saccharin or quinine. Null mutant mice of both sexes demonstrated longer duration of ethanol-induced loss of righting reflex (LORR), and males were more sensitive to ethanol-induced motor sedation. In contrast, [rho]1 null mice showed faster recovery from acute motor incoordination produced by ethanol. Null mutant females were less sensitive to ethanol-induced development of conditioned taste aversion. Measurement of mRNA levels in cerebellum showed that deletion of [rho]1 did not change expression of [rho]2, [alpha]2, or [alpha]6 GABA.sub.A receptor subunits. (S)-4-amino-cyclopent-1-enyl butylphosphinic acid ("[rho]1" antagonist), when administered to wild type mice, mimicked the changes that ethanol induced in [rho]1 null mice (LORR and rotarod tests), but the [rho]1 antagonist did not produce these effects in [rho]1 null mice. In contrast, (R)-4-amino-cyclopent-1-enyl butylphosphinic acid ("[rho]2" antagonist) did not change ethanol actions in wild type but produced effects in mice lacking [rho]1 that were opposite of the effects of deleting (or inhibiting) [rho]1. These results suggest that [rho]1 has a predominant role in two in vivo effects of ethanol, and a role for [rho]2 may be revealed when [rho]1 is deleted. We also found that ethanol produces similar inhibition of function of recombinant [rho]1 and [rho]2 receptors. These data indicate that ethanol action on GABA.sub.A receptors containing [rho]1/[rho]2 subunits may be important for specific effects of ethanol in vivo.