GABAA receptors containing p1 subunits contribute to in vivo effects of ethanol in mice

Abstract

GABAA receptors consisting of p1, p2, or p3 subunits in homo- or hetero-pentamers have been studied mainly in retina but are detected in many brain regions. Receptors formed from p1 are inhibited by low ethanol concentrations, and familybased association analyses have linked p subunit genes with alcohol dependence. We determined if genetic deletion of p1 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, p1 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 p1 did not change expression of p2, α2, or α6 GABA A receptor subunits. (S)-4-amino-cyclopent-1-enyl butylphosphinic acid ("p1" antagonist), when administered to wild type mice, mimicked the changes that ethanol induced in p1 null mice (LORR and rotarod tests), but the p1 antagonist did not produce these effects in p1 null mice. In contrast, (R)-4-amino-cyclopent-1-enyl butylphosphinic acid ("p2" antagonist) did not change ethanol actions in wild type but produced effects in mice lacking p1 that were opposite of the effects of deleting (or inhibiting) p1. These results suggest that p1 has a predominant role in two in vivo effects of ethanol, and a role for p2 may be revealed when p1 is deleted. We also found that ethanol produces similar inhibition of function of recombinant p1 and p2 receptors. These data indicate that ethanol action on GABAA receptors containing p1/p2 subunits may be important for specific effects of ethanol in vivo. © 2014 Blednov et al.