5-HT 1A/1B receptor-mediated effects of the selective serotonin reuptake inhibitor, citalopram, on sleep: studies in 5-HT 1A and 5-HT 1B knockout mice.
Selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of depression. Aside from their antidepressant properties, they provoke a deficit in paradoxical sleep (PS) that is most probably mediated by the transporter blockade-induced increase in serotonin concentration in the extracellular space. Such an effect can be accounted for by the action of serotonin at various types of serotonergic receptors involved in PS regulation, among which the 5-HT(1A) and 5-HT(1B) types are the best candidates. According to this hypothesis, we examined the effects of citalopram, the most selective SSRI available to date, on sleep in the mouse after inactivation of 5-HT(1A) or 5-HT(1B) receptors, either by homologous recombination of their encoding genes, or pharmacological blockade with selective antagonists. For this purpose, sleep parameters of knockout mice that do not express these receptors and their wild-type counterparts were monitored during 8 h after injection of citalopram alone or in association with 5-HT(1A) or 5-HT(1B) receptor antagonists. Citalopram induced mainly a dose-dependent inhibition of PS during 2-6 h after injection, which was observed in wild-type and 5-HT(1B)-/- mice, but not in 5-HT(1A)-/- mutants. This PS inhibition was fully antagonized by pretreatment with the 5-HT(1A) antagonist WAY 100635, but only partially with the 5-HT(1B) antagonist GR 127935. These data indicate that the action of the SSRI citalopram on sleep in the mouse is essentially mediated by 5-HT(1A) receptors. Such a mechanism of action provides further support to the clinical strategy of antidepressant augmentation by 5-HT(1A) antagonists, because the latter would also counteract the direct sleep-inhibitory side-effects of SSRIs.
Monaca
Christelle
C
INSERM U288, NeuroPsychoPharmacologie Moléculaire Cellulaire et Fonctionnelle, CHU Pitié-Salpêtrière-91, Boulevard de l'Hôpital, 75013 Paris, France.
Boutrel
Benjamin
B
Hen
René
R
Hamon
Michel
M
Adrien
Joëlle
J
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D015283:Citalopram / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000172:deficiency* / Q000235:genetics; D044263:Receptors, Serotonin, 5-HT1; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D012894:Sleep Stages / Q000187:drug effects* / Q000502:physiology
D002352:Carrier Proteins; D015283:Citalopram; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse