GABAA receptors containing ?1 subunits contribute to in vivo effects of ethanol in mice.

ABSTRACT: GABAA receptors consisting of ?1, ?2, or ?3 subunits in homo- or hetero-pentamers have been studied mainly in retina but are detected in many brain regions. Receptors formed from ?1 are inhibited by low ethanol concentrations, and family-based association analyses have linked ? subunit genes with alcohol dependence. We determined if genetic deletion of ?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, ?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 ?1 did not change expression of ?2, ?2, or ?6 GABAA receptor subunits. (S)-4-amino-cyclopent-1-enyl butylphosphinic acid ("?1" antagonist), when administered to wild type mice, mimicked the changes that ethanol induced in ?1 null mice (LORR and rotarod tests), but the ?1 antagonist did not produce these effects in ?1 null mice. In contrast, (R)-4-amino-cyclopent-1-enyl butylphosphinic acid ("?2" antagonist) did not change ethanol actions in wild type but produced effects in mice lacking ?1 that were opposite of the effects of deleting (or inhibiting) ?1. These results suggest that ?1 has a predominant role in two in vivo effects of ethanol, and a role for ?2 may be revealed when ?1 is deleted. We also found that ethanol produces similar inhibition of function of recombinant ?1 and ?2 receptors. These data indicate that ethanol action on GABAA receptors containing ?1/?2 subunits may be important for specific effects of ethanol in vivo.

SUBMITTER: Blednov YA 

PROVIDER: S-EPMC3894180 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature