GABAA Receptors Containing ρ1 Subunits Contribute to In Vivo Effects of Ethanol in Mice

GABA(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(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(A) receptors containing rho 1/rho 2 subunits may be important for specific effects of ethanol in vivo.