Key Role of 5-HT1BReceptors in the Regulation of Paradoxical Sleep as Evidenced in 5-HT1BKnock-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_1Aagonist 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.