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Journal of Neural Transmission

, Volume 120, Issue 1, pp 169–176 | Cite as

Differential adaptation of REM sleep latency, intermediate stage and theta power effects of escitalopram after chronic treatment

  • Szilvia Vas
  • Zita Kátai
  • Diána Kostyalik
  • Dorottya Pap
  • Eszter Molnár
  • Péter Petschner
  • Lajos Kalmár
  • György Bagdy
Basic Neurosciences, Genetics and Immunology - Original Article

Abstract

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.

Keywords

SSRI Escitalopram Rapid eye movement (REM) sleep 5-HT1A receptor Intermediate stage of sleep Chronic treatment 

Notes

Acknowledgments

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.

References

  1. 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
  2. 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
  3. 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
  4. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38(8):1083–1152. doi: S0028390899000106 PubMedCrossRefGoogle Scholar
  5. 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
  6. 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
  7. Dumont GJ, de Visser SJ, Cohen AF, van Gerven JM (2005) Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects. Br J Clin Pharmacol 59(5):495–510. doi: BCP234210.1111/j.1365-2125.2005.02342.x PubMedCrossRefGoogle Scholar
  8. Feige B, Voderholzer U, Riemann D, Dittmann R, Hohagen F, Berger M (2002) Fluoxetine and sleep EEG: effects of a single dose, subchronic treatment, and discontinuation in healthy subjects. Neuropsychopharmacology 26(2):246–258. doi: S0893133X0100314110.1016/S0893-133X(01)00314-1 PubMedCrossRefGoogle Scholar
  9. 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-x PubMedCrossRefGoogle Scholar
  10. 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)00015-4 PubMedCrossRefGoogle Scholar
  11. 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
  12. 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
  13. 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
  14. Graf M, Jakus R, Kantor S, Levay G, Bagdy G (2004) Selective 5-HT1A and 5-HT7 antagonists decrease epileptic activity in the WAG/Rij rat model of absence epilepsy. Neurosci Lett 359(1–2):45–48. doi: S030439400400166110.1016/j.neulet.2004.01.072 PubMedCrossRefGoogle Scholar
  15. Ivarsson M, Paterson LM, Hutson PH (2005) Antidepressants and REM sleep in Wistar-Kyoto and Sprague-Dawley rats. Eur J Pharmacol 522(1–3):63–71. doi: S0014-2999(05)00852-610.1016/j.ejphar.2005.08.050 PubMedCrossRefGoogle Scholar
  16. 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: S0006899302026987 PubMedCrossRefGoogle Scholar
  17. Kantor S, Jakus R, Balogh B, Benko A, Bagdy G (2004) Increased wakefulness, motor activity and decreased theta activity after blockade of the 5-HT2B receptor by the subtype-selective antagonist SB-215505. Br J Pharmacol 142(8):1332–1342. doi: sj.bjp.070588710.1038/sj.bjp.0705887 PubMedCrossRefGoogle Scholar
  18. 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.105.086413 PubMedCrossRefGoogle Scholar
  19. 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
  20. Kitka T, Katai Z, Pap D, Molnar E, Adori C, Bagdy G (2009) Small platform sleep deprivation selectively increases the average duration of rapid eye movement sleep episodes during sleep rebound. Behav Brain Res 205(2):482–487. doi: S0166-4328(09)00471-910.1016/j.bbr.2009.08.004 PubMedCrossRefGoogle Scholar
  21. Lader M, Andersen HF, Baekdal T (2005) The effect of escitalopram on sleep problems in depressed patients. Hum Psychopharmacol 20(5):349–354. doi: 10.1002/hup.694 PubMedCrossRefGoogle Scholar
  22. Landolt HP, de Boer LP (2001) Effect of chronic phenelzine treatment on REM sleep: report of three patients. Neuropsychopharmacology 25(5 Suppl):S63–S67. doi: S0893133X0100321910.1016/S0893-133X(01)00321-9 PubMedCrossRefGoogle Scholar
  23. 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
  24. 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.13001091300109 PubMedGoogle Scholar
  25. 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
  26. Oswald I, Adam K (1986) Effects of paroxetine on human sleep. Br J Clin Pharmacol 22(1):97–99PubMedGoogle Scholar
  27. Owens MJ, Knight DL, Nemeroff CB (2001) Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry 50(5):345–350. doi: S0006-3223(01)01145-3 PubMedCrossRefGoogle Scholar
  28. Popa D, Lena C, Alexandre C, Adrien J (2008) Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior. J Neurosci 28(14):3546–3554. doi: 10.1523/jneurosci.4006-07.2008 PubMedCrossRefGoogle Scholar
  29. Sanchez C, Brennum LT, Storustovu S, Kreilgard M, Mork A (2007) Depression and poor sleep: the effect of monoaminergic antidepressants in a pre-clinical model in rats. Pharmacol Biochem Behav 86(3):468–476. doi: S0091-3057(07)00022-610.1016/j.pbb.2007.01.006 PubMedCrossRefGoogle Scholar
  30. Sharpley AL, Williamson DJ, Attenburrow ME, Pearson G, Sargent P, Cowen PJ (1996) The effects of paroxetine and nefazodone on sleep: a placebo controlled trial. Psychopharmacology (Berl) 126(1):50–54CrossRefGoogle Scholar
  31. Sommerfelt L (1990) Chronic zimeldine administration to cats: sustained increase of serotonergic effect as measured with sleep parameters. Pharmacol Toxicol 66(2):128–132PubMedCrossRefGoogle Scholar
  32. Steiger A, Kimura M (2010) Wake and sleep EEG provide biomarkers in depression. J Psychiatr Res 44(4):242–252. doi: S0022-3956(09)00189-710.1016/j.jpsychires.2009.08.013 PubMedCrossRefGoogle Scholar
  33. Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340(2–3):249–258. doi: S0014-2999(97)01393-9 PubMedCrossRefGoogle Scholar
  34. 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: jsr002002103 PubMedCrossRefGoogle Scholar
  35. 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
  36. Wade A, Friis Andersen H (2006) The onset of effect for escitalopram and its relevance for the clinical management of depression. Curr Med Res Opin 22(11):2101–2110. doi: 10.1185/030079906X148319 PubMedCrossRefGoogle Scholar
  37. Waugh J, Goa KL (2003) Escitalopram: a review of its use in the management of major depressive and anxiety disorders. CNS Drugs 17(5):343–362. doi: 1754 PubMedCrossRefGoogle Scholar
  38. Wilson S, Argyropoulos S (2005) Antidepressants and sleep: a qualitative review of the literature. Drugs 65(7):927–947PubMedCrossRefGoogle Scholar
  39. Wilson SJ, Bailey JE, Rich AS, Adrover M, Potokar J, Nutt DJ (2004) Using sleep to evaluate comparative serotonergic effects of paroxetine and citalopram. Eur Neuropsychopharmacol 14(5):367–372. doi: S0924977X0300221910.1016/j.euroneuro.2003.11.004 PubMedCrossRefGoogle Scholar
  40. Winokur A, Gary KA, Rodner S, Rae-Red C, Fernando AT, Szuba MP (2001) Depression, sleep physiology, and antidepressant drugs. Depress Anxiety 14(1):19–28. doi: 10.1002/da.1043 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Szilvia Vas
    • 1
  • Zita Kátai
    • 1
  • Diána Kostyalik
    • 1
  • Dorottya Pap
    • 1
  • Eszter Molnár
    • 1
  • Péter Petschner
    • 1
  • Lajos Kalmár
    • 2
  • György Bagdy
    • 1
    • 3
    • 4
  1. 1.Department of PharmacodynamicsSemmelweis UniversityBudapestHungary
  2. 2.Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesBudapestHungary
  3. 3.Group of NeurochemistryHungarian Academy of SciencesBudapestHungary
  4. 4.Group of NeuropsychopharmacologyHungarian Academy of SciencesBudapestHungary

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