Alpha1- and alpha2-containing GABA(A) receptor modulation is not necessary for benzodiazepine-induced hyperphagia

Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatability. We investigated which GABAA receptor subtypes may be involved in mediating benzodiazepine-induced hyperphagia. The role of the a2 subtype was investigated by observing the effects of midazolam, on the behavioural satiety sequence in mice with targeted deletion of the a2 gene (a2 knockout). Midazolam (0.125, 0.25 and 0.5 mg/kg) increased food intake and the amount of time spent feeding in a2 knockout mice, suggesting that BZ-induced hyperphagia does not involve a2-containing GABAA receptors. We further investigated the roles of a1- and a3-containing GABAA receptors in mediating BZ-induced hyperphagia. We treated a2(H101R) mice, in which a2-containing receptors are rendered benzodiazepine insensitive, with L-838417, a compound which acts as a partial agonist at a2-, a3- and a5-receptors but is inactive at a1-containing receptors. L-838417 (10 and 30 mg/kg) increased food intake and the time spent feeding in both wildtype and a2(H101R) mice, demonstrating that benzodiazepine-induced hyperphagia does not require a1- and a2-containing GABAA receptors. These observations, together with evidence against the involvement of a5-containing GABAA receptors, suggest that a3-containing receptors mediate BZ-induced hyperphagia in the mouse.