The effects of the widely used selective serotonin reuptake inhibitor (SSRI) antidepressants on sleep have been intensively investigated. However, only a few animal studies examined the effect of escitalopram, the more potent S-enantiomer of citalopram, and conclusions of these studies on sleep architecture are limited due to the experimental design. Here, we investigate the acute (2 and 10 mg/kg, i.p. injected at the beginning of the passive phase) or chronic (10 mg/kg/day for 21 days, by osmotic minipumps) effects of escitalopram on the sleep and quantitative electroencephalogram (EEG) of Wistar rats. The first 3 h of EEG recording was analyzed at the beginning of passive phase, immediately after injections. The acutely injected 2 and 10 mg/kg and the chronically administered 10 mg/kg/day escitalopram caused an approximately three, six and twofold increases in rapid eye movement sleep (REMS) latency, respectively. Acute 2-mg/kg escitalopram reduced REMS, but increased intermediate stage of sleep (IS) while the 10 mg/kg reduced both. We also observed some increase in light slow wave sleep and passive wake parallel with a decrease in deep slow wave sleep and theta power in both active wake and REMS after acute dosing. Following chronic treatment, only the increase in REMS latency remained significant compared to control animals. In conclusion, adaptive changes in the effects of escitalopram, which occur after 3 weeks of treatment, suggest desensitization in the function of 5-HT1A and 5-HT1B receptors.
SSRI Escitalopram Rapid eye movement (REM) sleep 5-HT1A receptor Intermediate stage of sleep Chronic treatment
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This work was supported by the 6th Framework Program of the European Community LSHM-CT-2004-503474, Hungarian Research Fund Grant T020500, Ministry of Welfare Research Grant 460/2006, TAMOP-2.2.1. B-09/1/KMR-2010-0001(G.B.).
Conflict of interest
The authors declare that they have no conflict of interest.
Acsady L, Arabadzisz D, Katona I, Freund TF (1996) Topographic distribution of dorsal and median raphe neurons with hippocampal, septal and dual projection. Acta Biol Hung 47(1–4):9–19PubMedGoogle Scholar
Bagdy G (1998) Serotonin, anxiety, and stress hormones. Focus on 5-HT receptor subtypes, species and gender differences. Ann NY Acad Sci 851:357–363PubMedCrossRefGoogle Scholar
Bagdy E, Harsing LG Jr (1995) The role of various calcium and potassium channels in the regulation of somatodendritic serotonin release. Neurochem Res 20(12):1409–1415PubMedCrossRefGoogle Scholar
Blier P, De Montigny C, Azzaro AJ (1986) Modification of serotonergic and noradrenergic neurotransmissions by repeated administration of monoamine oxidase inhibitors: electrophysiological studies in the rat central nervous system. J Pharmacol Exp Ther 237(3):987–994PubMedGoogle Scholar
Chaput Y, Blier P, de Montigny C (1986) In vivo electrophysiological evidence for the regulatory role of autoreceptors on serotonergic terminals. J Neurosci 6(10):2796–2801PubMedGoogle Scholar
Felton TM, Kang TB, Hjorth S, Auerbach SB (2003) Effects of selective serotonin and serotonin/noradrenaline reuptake inhibitors on extracellular serotonin in rat diencephalon and frontal cortex. Naunyn Schmiedebergs Arch Pharmacol 367(3):297–305. doi:10.1007/s00210-002-0688-xPubMedCrossRefGoogle Scholar
Filakovszky J, Gerber K, Bagdy G (1999) A serotonin-1A receptor agonist and an N-methyl-d-aspartate receptor antagonist oppose each others effects in a genetic rat epilepsy model. Neurosci Lett 261(1–2):89–92. doi:S0304-3940(99)00015-4PubMedCrossRefGoogle Scholar
Gauthier P, Arnaud C, Stutzmann JM, Gottesmann C (1997) Influence of zopiclone, a new generation hypnotic, on the intermediate stage and paradoxical sleep in the rat. Psychopharmacology (Berl) 130(2):139–143CrossRefGoogle Scholar
Gillin JC, Jernajczyk W, Valladares-Neto DC, Golshan S, Lardon M, Stahl SM (1994) Inhibition of REM sleep by ipsapirone, a 5HT1A agonist, in normal volunteers. Psychopharmacology (Berl) 116(4):433–436CrossRefGoogle Scholar
Gottesmann C, Gandolfo G, Arnaud C, Gauthier P (1998) The intermediate stage and paradoxical sleep in the rat: influence of three generations of hypnotics. Eur J Neurosci 10(2):409–414PubMedCrossRefGoogle Scholar
Kantor S, Jakus R, Bodizs R, Halasz P, Bagdy G (2002) Acute and long-term effects of the 5-HT2 receptor antagonist ritanserin on EEG power spectra, motor activity, and sleep: changes at the light-dark phase shift. Brain Res 943(1):105–111. doi:S0006899302026987PubMedCrossRefGoogle Scholar
Kantor S, Jakus R, Molnar E, Gyongyosi N, Toth A, Detari L, Bagdy G (2005) Despite similar anxiolytic potential, the 5-hydroxytryptamine 2C receptor antagonist SB-242084 [6-chloro-5-methyl-1-[2-(2-methylpyrid-3-yloxy)-pyrid-5-yl carbamoyl] indoline] and chlordiazepoxide produced differential effects on electroencephalogram power spectra. J Pharmacol Exp Ther 315(2):921–930. doi:jpet.105.08641310.1124/jpet.105.086413PubMedCrossRefGoogle Scholar
Kitka TBG (2008) Effect of 5-HT2A/2B/2C receptor agonists and antagonists on sleep and waking in laboratory animals and humans. In: Monti JM, Pandi-Perumal SR, Jacobs BL, Nutt DJ (eds) Serotonin and sleep: molecular functional and clinical aspects. Birkhäuser Verlag, Switzerland, pp 387–414CrossRefGoogle Scholar
Maudhuit C, Jolas T, Lainey E, Hamon M, Adrien J (1994) Effects of acute and chronic treatment with amoxapine and cericlamine on the sleep-wakefulness cycle in the rat. Neuropharmacology 33(8):1017–1025PubMedCrossRefGoogle Scholar
Monaca C, Boutrel B, Hen R, Hamon M, Adrien J (2003) 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. Neuropsychopharmacology 28(5):850–856. doi:10.1038/sj.npp.13001091300109PubMedGoogle Scholar
Neckelmann D, Bjorvatn B, Bjorkum AA, Ursin R (1996) Citalopram: differential sleep/wake and EEG power spectrum effects after single dose and chronic administration. Behav Brain Res 79(1–2):183–192PubMedCrossRefGoogle Scholar
Oswald I, Adam K (1986) Effects of paroxetine on human sleep. Br J Clin Pharmacol 22(1):97–99PubMedGoogle Scholar
Tissier MH, Lainey E, Fattaccini CM, Hamon M, Adrien J (1993) Effects of ipsapirone, a 5-HT1A agonist, on sleep/wakefulness cycles: probable post-synaptic action. J Sleep Res 2(2):103–109. doi:jsr002002103PubMedCrossRefGoogle Scholar
van Bemmel AL, van den Hoofdakker RH, Beersma DG, Bouhuys AL (1993) Changes in sleep polygraphic variables and clinical state in depressed patients during treatment with citalopram. Psychopharmacology (Berl) 113(2):225–230CrossRefGoogle Scholar