Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice.
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.
Boutrel
Benjamin
B
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. boutrel@hotmail.com
Monaca
Christelle
C
Hen
Rene
R
Hamon
Michel
M
Adrien
Joelle
J
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D001143:Arousal / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D004569:Electroencephalography; D004585:Electrooculography; D006706:Homeostasis / Q000502:physiology*; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012149:Restraint, Physical; D018490:Serotonin Agents / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D012892:Sleep Deprivation; D012895:Sleep, REM / Q000502:physiology*; D013312:Stress, Physiological / Q000503:physiopathology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin