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The Journal of Neuroscience, June 1, 2002, 22(11):4686-4692

Involvement of 5-HT_1A Receptors in Homeostatic and Stress-Induced Adaptive Regulations of Paradoxical Sleep: Studies in 5-HT_1A Knock-Out Mice

Benjamin Boutrel, Christelle Monaca, René Hen², Michel Hamon, and Joëlle Adrien

Institut National de la Santé et de la Recherche Médicale U288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médicine Pitié-Salpêtrière, 75634 Paris Cedex 13, France, and ² Center for Neurobiology and Behavior, Columbia University, New York, New York 10032

For the last two decades, the involvement of 5-HT_1A receptors 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-HT_1A/) and their wild-type 129/Sv counterparts, we herein demonstrate that 5-HT_1A 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-HT_1A/ 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-HT_1A receptors by WAY 100635 (0.5 mg/kg, i.p.) promoted paradoxical sleep, whereas the 5-HT_1A agonist 8-OH-DPAT (0.25-1 mg/kg, s.c.) had an opposite effect. In contrast, none of the 5-HT_1A receptor ligands affected sleep significantly in 5-HT_1A/ mice. However, 5-HT_1B 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-HT_1A/ mutants. Finally, in contrast to wild-type mice, 5-HT_1A/ 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-HT_1A receptors participate in the spontaneous and homeostatic regulation, as well as in stress-induced adaptive changes of paradoxical sleep.

Key words: sleep-wakefulness; 5-HT_1A receptors; sleep deprivation; immobilization stress; knock-out mice; paradoxical sleep homeostasis

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22114686-07$05.00/0

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