Flumazenil but not FG7142 reverses the decrease in pentobarbital sleep caused by activation of central noradrenergic...

Central noradrenergic systems have been shown to modulate the hypnotic activity of pentobarbital in mice. To determine whether the GABA(A)/benzodiazepine receptor system is involved in the decrease in pentobarbital sleep caused by activation of central noradrenergic systems, we examined in mice the effects of the benzodiazepine receptor ligands flumazenil and FG7142 on pentobarbital-induced sleep, and on adrenoceptor ligand modulation of pentobarbital sleep. The intracerebroventricular (i.c.v.) administration of methoxamine (8-200 nmol), an alpha1-adrenoceptor agonist, and yohimbine (1-30 nmol), an alpha2-adrenoceptor antagonist, produced a dose-dependent decrease in sleeping time induced by pentobarbital (50 mg/kg, intraperitoneally (i.p.)). The i.c.v. administration of flumazenil (16.5 and 33 nmol), a selective benzodiazepine receptor antagonist, had no effect on pentobarbital sleep, whereas an i.p. injection of FG7142, a selective benzodiazepine receptor inverse agonist, shortened pentobarbital sleep. Flumazenil (33 nmol, i.c.v.) caused the pentobarbital sleep time, shortened by methoxamine (200 nmol, i.c.v.) and yohimbine (30 nmol, i.c.v.), to return to the control level, while FG7142 (10 mg/kg, i.p.) had no effect on the methoxamine- and yohimbine-shortened pentobarbital sleep. These results suggest that putative endogenous benzodiazepine receptor ligands with an inverse agonist-like property are involved in the methoxamine- and yohimbine-induced decrease in pentobarbital sleep in mice.