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The Journal of Neuroscience, December 7, 2005, 25(49):11231-11238; doi:10.1523/JNEUROSCI.1724-05.2005

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Behavioral/Systems/Cognitive
Contribution of 5-HT₂ Receptor Subtypes to Sleep–Wakefulness and Respiratory Control, and Functional Adaptations in Knock-Out Mice Lacking 5-HT_2A Receptors

Daniela Popa,¹ Clément Léna,⁴ Véronique Fabre,¹ Caroline Prenat,² Jay Gingrich,³ Pierre Escourrou,² Michel Hamon,¹ and Joëlle Adrien¹

¹Unité Mixte de Recherche 677, Institut National de la Santé et de la Recherche Médicale/Universite Pierre et Marie Curie, 75013 Paris, France, ²Équipe Associée 3544, Institut Fédératif de Recherche–Institut de Signalisation et Innovation Thérapeutique, 92296 Chatenay-Malabry, France, ³Department of Psychiatry, Columbia University, New York, New York 10032, and ⁴Unité Mixte de Recherche 8544, École Normale Supérieure, 75005 Paris, France

Serotonin (5-hydroxytryptamine; 5-HT) plays key roles in sleep–wakefulness regulation. Evidence indicates that 5-HT₂ receptors are involved mainly in non-rapid eye movement sleep (NREMS) regulation and respiratory control. Here, we investigated the relative contribution of 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor subtypes to NREMS and breathing during sleep, using 5-HT₂ subtype-selective ligands in wild-type (5-HT_2A+/+) and knock-out (5-HT_2A–/–) mice that do not express 5-HT_2A receptors. Acute blockade of 5-HT_2A receptors induced an increase in NREMS in 5-HT_2A+/+ mice, but not 5-HT_2A–/– mutants, which spontaneously expressed less NREMS than wild-type animals. In 5-HT_2A+/+ mice, 5-HT_2B receptor blockade produced a reduction of NREMS, whereas receptor activation induced an increase in this sleep stage. These effects were less pronounced in 5-HT_2A–/– mice, indicating a lower sensitivity of 5-HT_2B receptors in mutants, with no change in 5-HT_2B mRNA. Blockade of 5-HT_2C receptors had no effect on NREMS in both strains. In addition, an increase in EEG power density after sleep deprivation was observed in 5-HT_2A+/+ mice but not in 5-HT_2A–/– mice. Whole-body plethysmographic recordings indicated that 5-HT_2A receptor blockade in 5-HT_2A+/+ mice reduced NREMS apneas and bradypneas that occurred after sighs. In contrast, in 5-HT_2A–/– mutants, NREMS apneas were not modified, and bradypnea after sighs were more pronounced. Our results demonstrate that 5-HT exerts a 5-HT_2B-mediated facilitation of NREMS, and an influence respectively inhibitory on NREMS and facilitatory on sleep apnea generation, via 5-HT_2A receptors. Moreover, 5-HT_2A gene knock-out leads to functional compensations yielding adaptive changes opposite to those caused by pharmacological blockade of 5-HT_2A receptors in 5-HT_2A+/+ mice.

Key words: serotonin; sleep; mice; 5-HT₂ receptors; sleep deprivation; apnea; respiration; serotonergic; depression; knock-out mice; EEG

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Received April 29, 2005; revised October 6, 2005; accepted October 7, 2005.

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