Molecular and neuronal substrate for the selective attenuation of anxiety

Benzodiazepine tranquilizers are used in the treatment of anxiety disorders. To identify the molecular and neuronal target mediating the anxiolytic action of benzodiazepines, we generated and analyzed two mouse lines in which the alpha 2 or alpha 3 GABA(A) (gamma-aminobutyric acid type A) receptors, respectively, were rendered insensitive to diazepam by a knock-in point mutation. The anxiolytic action of diazepam was absent in mice with the alpha 2(H101R) point mutation but present in mice with the alpha 3(H126R) point mutation. These findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by alpha 2 GABA(A) receptors, which are largely expressed in the limbic system, but not by alpha 3 GABA(A) receptors, which predominate in the reticular activating system.