Key role of 5-HT(1B) receptors in the regulation of paradoxical sleep as evidenced in 5-HT(1B) knock-out mice

Abstract

The involvement of 5-HT(1B) receptors in the regulation of vigilance states was assessed by investigating the spontaneous sleep-waking cycles and the effects of 5-HT receptor ligands on sleep in knock-out (5-HT(1B)-/-) mice that do not express this receptor type. Both 5-HT(1B)-/- and wild-type 129/Sv mice exhibited a clear-cut diurnal sleep-wakefulness rhythm, but knock-out animals were characterized by higher amounts of paradoxical sleep and lower amounts of slow-wave sleep during the light phase and by a lack of paradoxical sleep rebound after deprivation. In wild-type mice, the 5-HT(1B) agonists CP 94253 (1-10 mg/kg, i.p.) and RU 24969 (0.25-2.0 mg/kg, i.p.) induced a dose-dependent reduction of paradoxical sleep during the 2-6 hr after injection, whereas the 5-HT(1B/1D) antagonist GR 127935 (0.1-1.0 mg/kg, i.p.) enhanced paradoxical sleep. In addition, pretreatment with GR 127935, but not with the 5-HT(1A) antagonist WAY 100635, prevented the effects of both 5-HT(1B) agonists. In contrast, none of the 5-HT(1B) receptor ligands, at the same doses as those used in wild-type mice, had any effect on sleep in 5-HT(1B)-/- mutants. Finally, the 5-HT(1A) agonist 8-OH-DPAT (0.2-1.2 mg/kg, s.c.) induced in both strains a reduction in the amount of paradoxical sleep. Altogether, these data indicate that 5-HT(1B) receptors participate in the regulation of paradoxical sleep in the mouse.