Diazepam-induced changes on sleep and the EEG spectrum in mice: role of the alpha3-GABA(A) receptor subtype.
Benzodiazepines reduce EEG slow-wave activity in non-REM sleep by potentiating GABAergic neurotransmission at GABAA receptors via a modulatory binding site. However, the mechanisms of action underlying the effects of benzodiazepines on sleep and the sleep EEG are still unknown. Slow waves during sleep are generated by the corticothalamic system and synchronized by the inhibitory GABAergic neurons of the reticular thalamic nucleus. This region contains exclusively alpha3-containing GABAA receptors. We investigated the role of these receptors in the mediation of diazepam effects on the sleep EEG by studying point-mutated mice in which the alpha3-GABAA receptor is diazepam-insensitive [alpha3(H126R)]. Sleep was recorded for 12 h after i.p. injection of 3 mg/kg diazepam or vehicle at light onset in alpha3(H126R) and wild-type controls (n = 13-17 per genotype). The main effect was a marked reduction of slow-wave activity (EEG power density in 0.75-4.00 Hz) in non-REM sleep and a concomitant increase in frequencies above 15.00 Hz in non-REM sleep and waking in both genotypes. Neither effect of diazepam differed significantly between the genotypes. Despite the exclusive expression of alpha3-containing GABAA receptors in the reticular thalamic nucleus, these receptors do not seem to be critical for the mediation of the effects of diazepam on the sleep EEG.
Kopp
C
C
Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
Rudolph
U
U
Keist
R
R
Tobler
I
I
D000818:Animals; D003975:Diazepam / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D018757:GABA Modulators / Q000494:pharmacology*; D020646:Intralaminar Thalamic Nuclei / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects*
D018757:GABA Modulators; D011963:Receptors, GABA-A; D003975:Diazepam