Modulation of rhythmic brain activity by diazepam: GABA(A) receptor subtype and state specificity

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is involved in the generation of various brain rhythmic activities that can be modulated by benzodiazepines. Here, we assessed the contribution of alpha(2)GABA type A (GABA(A)) receptors to the effects of benzodiazepines on sleep and waking oscillatory patterns by combining pharmacological and genetic tools. The effects of diazepam on the electroencephalogram were compared between alpha(2)(H101R) knock-in mice in which the alpha(2)GABA(A) receptor was rendered diazepam-insensitive, and their wild-type controls. The suppression of delta activity typically induced by diazepam in non-rapid eye movement (REM) sleep was significantly stronger in wild-type control mice than in alpha(2)(H101R) mice. Moreover, electroencephalogram frequency activity above 16-18 Hz was enhanced in wild-type mice both in non-REM sleep and waking. This effect was absent in alpha(2)(H101R) mice. Theta activity was enhanced after diazepam both in REM sleep and in waking in wild-type mice. In alpha(2)(H101R) mice, this effect was markedly reduced in REM sleep whereas it persisted in waking. These findings suggest that alpha(2)GABA(A) receptors, which are expressed in hypothalamic and pontine nuclei and in the hippocampus, are localized in distinct neural circuits relevant for the modulation of rhythmic brain activities by benzodiazepines.