Etomidate and propofol-hyposensitive GABAA receptor β3(N265M) mice show little changes in acute alcohol sensitivity but enhanced tolerance and withdrawal

Gamma-aminobutyric acid-A (GABA_A) receptors are ligand-gated ion channels comprised of subunits from several classes (alpha, beta, gamma, delta). Recent studies have clearly demonstrated that the functional properties of GABA_A receptors are altered following chronic ethanol administration that could provide the molecular basis for the previously proposed role of these receptors in ethanol tolerance and dependence. Because the subunit composition of GABA_A receptors determines receptor pharmacology, the present study was devoted to assess if the behavioral sensitivity after acute and chronic ethanol exposure depends on β3-containing GABA_A receptors. In the present study, we used knock-in mice harboring a point mutation (N265M) in the second transmembrane region of the β3 subunit of the GABA_A receptor in order to study acute and chronic behavioral effects of ethanol. More specifically, we tested tolerance to loss of righting reflex (LORR) and the development of withdrawal signs after chronic ethanol exposure using ethanol vapor chambers. Our results show that the β3(N265M) mutation does not play a major modulatory role of acute ethanol-induced LORR. However, following repeated LORR testing, enhanced tolerance to the intoxicating effects of ethanol was observed-a finding which was unrelated to the pharmacokinetics of ethanol as both genotypes had the same blood alcohol concentrations following repeated LORR testing. In addition, following chronic alcohol vapor exposure, mouse mutants displayed increased handling-induced convulsions during withdrawal. The results of the present study suggest that the alcohol effects abolished by the β3(N265M) mutation do not play a dominant role in acute alcohol intoxication but influence ethanol tolerance and withdrawal.