Normal acute behavioral responses to moderate/high dose ethanol in GABA_A receptor α4 subunit knockout mice

Background: γ-Aminobutyric acid type A receptors (GABA _A-Rs) have been implicated in mediating some of the behavioral effects of ethanol (EtOH), but the contribution of specific GABA_A-R subunits is not yet fully understood. The GABA_A-R α4 subunit often partners with β2/3 and δ subunits to form extrasynaptic GABA_A-Rs that mediate tonic inhibition. Several in vitro studies have suggested that these extrasynaptic GABA_A-Rs may be particularly relevant to the intoxicating effects of low doses of EtOH. In α4 subunit knockout mice, tonic inhibition was greatly reduced, as were the potentiating effects of EtOH. We therefore hypothesized that those behavioral responses to EtOH that are mediated by α4-containing GABA_A-Rs would be diminished in α4 knockout mice. Methods: We investigated behavioral responses to acute administration of moderate/high dose EtOH or pentylenetetrazol in α4 subunit knockout mice. We compared behavioral responses to EtOH in α4 knockout and wild-type littermates in the elevated plus maze (0.0, 1.0 g/kg EtOH), screen test (1.5, 2.0 g/kg), hypothermia (1.5, 2.0 g/kg), fixed speed rotarod (1.5, 2.0, 2.5 g/kg), open field (0.0, 1.0, 2.0 g/kg), radiant tail flick (2.0 g/kg), loss of righting reflex (3.5 g/kg), and EtOH metabolism and clearance assays. Sensitivity to pentylenetetrazol-induced seizures was also analyzed. Results: No differences were observed between α4 knockout mice and wild-type controls in terms of the baseline behavior in the absence of EtOH treatment or in the behavioral effects of EtOH in the assays tested. In contrast, α4 knockout mice were significantly more sensitive to pentylenetetrazol-induced seizures. Conclusions: We conclude that GABA_A-Rs containing the α4 subunit are not absolutely required for the acute behavioral responses to moderate/high dose EtOH that were assessed with the elevated plus maze, screen test, hypothermia, fixed speed rotarod, open field, radiant tail flick, and loss of right reflex assays. We further suggest that these findings are complicated by the demonstrated compensatory alterations in synaptic GABA_A-R EtOH sensitivity and function in α4 knockout mice.