Involvement of 5-HT1A Receptors in Homeostatic and Stress-Induced Adaptive Regulations of Paradoxical Sleep: Studies in 5-HT1A Knock-Out Mice

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Abstract
For the last two decades, the involvement of 5-HT1Areceptors in the regulation of vigilance states has been studied extensively thanks to pharmacological tools, but clear-cut conclusion has not been reached yet. By studying mutant mice that do not express this receptor type (5-HT1A−/−) and their wild-type 129/Sv counterparts, we herein demonstrate that 5-HT1A receptors play key roles in the control of spontaneous sleep–wakefulness cycles, as well as in homeostatic regulation and stress-induced adaptive changes of paradoxical sleep. Both strains of mice exhibited a diurnal sleep–wakefulness rhythm, but 5-HT1A−/− animals expressed higher amounts of paradoxical sleep than wild-type mice during both the light and the dark phases. In wild-type mice, pharmacological blockade of 5-HT1A receptors by WAY 100635 (0.5 mg/kg, i.p.) promoted paradoxical sleep, whereas the 5-HT1A agonist 8-OH-DPAT (0.25–1 mg/kg, s.c.) had an opposite effect. In contrast, none of the 5-HT1A receptor ligands affected sleep significantly in 5-HT1A−/− mice. However, 5-HT1B receptor stimulation by CP 94253 (1–3 mg/kg, i.p.) induced a reduction in paradoxical sleep in both strains, this effect being more pronounced in 5-HT1A−/− mutants. Finally, in contrast to wild-type mice, 5-HT1A−/− mutants did not exhibit any rebound of paradoxical sleep after either a 9 hr instrumental paradoxical sleep deprivation or a 90 min immobilization stress. Altogether, these data indicate that, in the mouse, 5-HT1A receptors participate in the spontaneous and homeostatic regulation, as well as in stress-induced adaptive changes of paradoxical sleep.