Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors.

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

1 CHU Pitié-Salpêtrière [AP-HP]
2 NEURO - Laboratoire de Neurobiologie (UMR 8544)
3 UN4-EA1544 - serotonine et neuropharmacologie
4 Gingich lab

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.

Domaines: Neurobiologie

Daniela Popa, Clément Léna, Véronique Fabre, Caroline Prenat, Jay Gingrich, et al.. Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors.. Journal of Neuroscience, 2005, 25 (49), pp.11231-8. ⟨10.1523/JNEUROSCI.1724-05.2005⟩. ⟨hal-00145492⟩