Animal experiments using manipulations of the α2-subunit in vivo have also suggested a more direct GABA-ethanol interaction but currently yield somewhat contradictory results. Using a knockout mouse model, deletion of the α2-subunit resulted in decreased sedation in response to an acute ethanol challenge, as measured by the loss of righting reflex [24], suggesting that the α2-subunit conveys sensitivity to the sedative effects of ethanol (though, curiously, it mediates stimulant effects of benzodiazepines [25], [26]). Mutations of the α2-subunit (S270I in transmembrane region 2 (TM2), A291W in TM3 [27] and α2(S270H, L277A) [22]) result in decreased ethanol potentiation of the GABA response in Xenopus oocytes. Mice bearing the latter mutation show reduced ethanol-induced locomotor activation and a corresponding increase in sedative effects as measured by loss of righting reflex [22]. Such results appear inconsistent with a decreased ethanol potentiation of GABA responses and with the behavioural data reported in knockout mice. Nevertheless these apparently contradictory data do suggest a potential role for the GABAA α2-subunit in several mechanisms that may contribute to the development of dependence to ethanol, including acute subjective responses to ethanol.
