GABA-A receptor subtypes, benzodiazepines and feeding

Benzodiazepines (BZs) enhance food intake by acting at GABAA receptors which have a pentameric structure consisting of two a, two ß and one ?2 subunit. a1, a2, a3, and a5 containing GABAA receptors are sensitive to BZs such as diazepam and midazolam. Cooper (2005) suggested that the effects of BZs on feeding were mediated by a2 or a3 containing GABAA receptors. We tested this hypothesis in two ways. In the first experiment we compared the effects of midazolam on feeding in WT mice and mice lacking the a2 subunit (a2 KO mice). There was a clear stimulation of feeding in the a2 KO mice, suggesting that a2 containing GABAA receptors are not essential to the hyperphagic response to BZs. In a second experiment we used the novel BZ L-838417, which acts as a partial agonist at a2, a3, and a5 containing GABAA receptors but is an antagonist at a1 containing GABAA containing receptors. The effects of L-838417 were compared in wild type and a2(H101R) mice, in which the a2 containing GABAA receptor is BZ-insensitive. L-838417 increased feeding in both groups of animals, thus excluding an involvement of either a1 or a2 containing GABAA receptors and suggesting that either a3 or a5 containing GABAA receptors mediate the hyperphagic effect of BZs. Older evidence suggests that the involvement of a5 containing GABAA receptors is unlikely. Thus our data confirm and extend Cooper's (2005) hypothesis by suggesting that the hyperphagic effect of BZs is mediated by a3 containing GABAA receptors.