Modulation of rhythmic brain activity by diazepam: GABA_A receptor subtype and state specificity

The inhibitory neurotransmitter γ-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 α ₂GABA 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 α₂(H101R) knock-in mice in which the α₂GABA_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 α 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 α₂(H101R) mice. Theta activity was enhanced after diazepam both in REM sleep and in waking in wild-type mice. In α₂(H101R) mice, this effect was markedly reduced in REM sleep whereas it persisted in waking. These findings suggest that α ₂GABA_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.