Genetically modified mice have also been used to assess the role of GABAA receptors in chronic tolerance. Recent work suggests that α1-GABAA receptors are involved in chronic tolerance to ethanol’s motor ataxic effects. GABAA receptor α1 (S270H, L277A) knockin mice that are initially less sensitive to ethanol’s motor ataxic effects display decreased tolerance after repeated ethanol exposure (Werner et al. 2009). Furthermore, β3-GABAA receptors appear to play a role in chronic tolerance. β3 (N265M) knockin mice display enhanced tolerance to ethanol’s sedative-hypnotic effects compared to controls (Sanchis-Segura et al. 2007). However, α6- and δ-GABAA receptor knockout mice do not differ from controls in chronic tolerance to ethanol’s sedative-hypnotic effects (Homanics et al. 1998; Mihalek et al. 2001). Studies have also been carried out in genetically modified mouse models of genes known to indirectly influence GABAA receptor function. Work has shown that PKCγ knockout mice did not develop chronic tolerance to ethanol’s sedative-hypnotic or hypothermic effects, but this response was strain dependent (Bowers et al. 1999). PKCε knockout mice are resistant to tolerance to motor-impairing effects of ethanol (Wallace et al.
