Such compensatory changes may be important when comparing data from other mutant mouse models. Differing mutations of the α2-subunit have resulted in both increased sedation in response to an ethanol challenge (S270H, L277A mutant [22]) and decreased sedation (H101R mutant [45]). The difference between these studies and the current data may be explained by a difficulty in identifying the mechanism by which ethanol is affecting GABAA transmission. Whether it is a direct mechanism or secondary effects via other neuromodulators, such as neurosteroids, manipulating different amino acid residues within the subunit may produce a variation in the receptor responses. However, it is noteworthy that a point mutation in α2-subunits (serine 270 to histidine and leucine 277 to alanine mutations) resulting in reduction of sensitivity to ethanol’s ability to facilitate GABA-induced current, when expressed in mice also enhanced ethanol’s effects on the loss of the righting reflex, without influencing ethanol consumption [22]. Since point mutations may be less likely to give rise to compensatory changes (but see [17]) than deletions, such a result would be consistent with the behavioural effects we observed being due to loss of α2-subunit function, and not to compensatory effects.
