Both α2 and α3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm

Abstract Mice with point‐mutated α2 GABA A receptor subunits (rendering them diazepam insensitive) are resistant to the anxiolytic‐like effects of benzodiazepines (BZs) in unconditioned models of anxiety. We investigated the role of the α2 GABA A subtype in a model of conditioned anxiety. α2(H101R) and wildtype mice were trained in a conditioned emotional response (CER) task, in which lever‐pressing for food on a variable interval (VI) schedule was suppressed during the presentation of a conditioned stimulus (CS+) that predicted footshock. The ability of diazepam, ethanol and pentobarbital to reduce suppression during the CS+ was interpreted as an anxiolytic response. Diazepam (0, 0.5, 1, 2, 4 and 8 mg/kg) induced a dose‐dependent anxiolytic‐like effect in wildtype mice. At high doses, diazepam (2, 4 and 8 mg/kg) was sedative in α2(H101R) mice. Analysis of the anxiolytic properties of nonsedative diazepam doses (0.5 and 1 mg/kg), showed that α2(H101R) mice were resistant to the anxiolytic effects of diazepam. Equivalent anxiolytic properties of pentobarbital (20 mg/kg) and ethanol (1 and 2 g/kg) were seen in both genotypes. These findings confirm the critical importance of the α2 GABA A subtype in mediating BZ anxiolysis. However, as a compound, L‐838417, with agonist properties at α2, α3 and α5‐containing receptors, gave rise to anxiolytic‐like activity in α2(H101R) mice in the CER test, α3‐containing GABA receptors are also likely to contribute to anxiolysis. Observations that α2(H101R) mice were more active, and displayed a greater suppression of lever pressing in response to fear‐conditioned stimuli than wildtype mice, suggests that the α2(H101R) mutation may not be behaviourally silent.