Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors.
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.
Popa
Daniela
D
Unité Mixte de Recherche 677, Institut National de la Santé et de la Recherche Médicale/Universite Pierre et Marie Curie, 75013 Paris, France. popa@ext.jussieu.fr
Léna
Clément
C
Fabre
Véronique
V
Prenat
Caroline
C
Gingrich
Jay
J
Escourrou
Pierre
P
Hamon
Michel
M
Adrien
Joëlle
J
D000222:Adaptation, Physiological / Q000235:genetics / Q000502:physiology*; D000818:Animals; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012123:Pulmonary Ventilation / Q000235:genetics / Q000502:physiology*; D044402:Receptor, Serotonin, 5-HT2A / Q000172:deficiency / Q000502:physiology; D044348:Receptors, Serotonin, 5-HT2 / Q000172:deficiency / Q000235:genetics*; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012892:Sleep Deprivation / Q000235:genetics / Q000378:metabolism; D014851:Wakefulness / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D044402:Receptor, Serotonin, 5-HT2A; D044348:Receptors, Serotonin, 5-HT2; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists