Diazepam-induced changes in sleep: Role of the alpha 1 GABA(A) receptor subtype

Ligands acting at the benzodiazepine (BZ) site of gamma -aminobutyric acid type A (GABA(A)) receptors currently are the most widely used hypnotics. BZ s such as diazepam (Dz) potentiate GABA(A) receptor activation. To determin e the GABA(A) receptor subtypes that mediate the hypnotic action of Dz wild -type mice and mice that harbor Dz-insensitive alpha1 GABA(A) receptors [al pha1 (H101R) mice] were compared.: Sleep latency and the amount of sleep af ter Dz treatment were not affected by the point mutation. An initial reduct ion of rapid eye movement (REM) sleep also occurred equally in both genotyp es, Furthermore, the Dz-induced changes in the sleep and waking electroence phalogram (EEG) spectra, the increase in power density above 21 Hz in non-R EM sleep and waking, and the suppression of slow-wave activity (SWA; EEG po wer in the 0.75- to 4.0-Hz band) in non-REM sleep were present in both geno types. Surprisingly, these effects were even more pronounced in alpha1(H101 R) mice and sleep continuity was enhanced by Dz only in the mutants. Intere stingly, Dz did not affect the initial surge of SWA at the transitions to s leep, indicating that the SWA-generating mechanisms are not impaired by the BZ. We conclude that the REM:sleep inhibiting action of Dz and its effect on the EEG spectra in sleep and waking are mediated by GABA(A) receptors ot her than alpha1, i,e., alpha2, alpha3, or alpha5 GABA(A) receptors, Because alpha1 GABA(A) receptors mediate the sedative action of Dz, our results pr ovide evidence that the hypnotic effect of Dz and its EEC "fingerprint" can be dissociated from its sedative action.