Experimental Brain Research

, Volume 232, Issue 3, pp 935–946 | Cite as

Chronic escitalopram treatment caused dissociative adaptation in serotonin (5-HT) 2C receptor antagonist-induced effects in REM sleep, wake and theta wave activity

  • Diána Kostyalik
  • Zita Kátai
  • Szilvia Vas
  • Dorottya Pap
  • Péter Petschner
  • Eszter Molnár
  • István Gyertyán
  • Lajos Kalmár
  • László Tóthfalusi
  • Gyorgy BagdyEmail author
Research Article


Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5–9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation.


SB-242084 REM sleep Theta waves Functional adaptation Anxiety Depression 



This study was supported by TAMOP-4.2.1. B-09/1/KMR-2010-0001 and by Richter Gedeon Plc.

Conflict of interest

The aforementioned funding agencies did not have any further role in study design, in the collection, analysis and interpretation of data, in writing of the report and in the decision to submit the paper for publication.


  1. Abramowski D, Rigo M, Duc D, Hoyer D, Staufenbiel M (1995) Localization of the 5-hydroxytryptamine2C receptor protein in human and rat brain using specific antisera. Neuropharmacology 34:1635–1645PubMedCrossRefGoogle Scholar
  2. Adrien J (2002) Neurobiological bases for the relation between sleep and depression. Sleep Med Rev 6:341–351PubMedGoogle Scholar
  3. Aston-Jones G, Bloom FE (1981) Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci 1:876–886PubMedGoogle Scholar
  4. Aulakh CS, Mazzola-Pomietto P, Murphy DL (1995) Long-term antidepressant treatments alter 5-HT2A and 5-HT2C receptor-mediated hyperthermia in Fawn-Hooded rats. Eur J Pharmacol 282:65–70PubMedCrossRefGoogle Scholar
  5. Bagdy G (1998) Serotonin, anxiety, and stress hormones: focus on 5-HT receptor subtypes, species and gender differences. Ann N Y Acad Sci 851:357–363PubMedCrossRefGoogle Scholar
  6. Bagdy G, Graf M, Anheuer ZE, Modos EA, Kantor S (2001) Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635. Int J Neuropsychopharmacol 4:399–408. doi: 10.1017/S1461145701002632 PubMedCrossRefGoogle Scholar
  7. Bagdy G, Kecskemeti V, Riba P, Jakus R (2007) Serotonin and epilepsy. J Neurochem 100:857–873. doi: 10.1111/j.1471-4159.2006.04277.x PubMedCrossRefGoogle Scholar
  8. Barker EL, Sanders-Bush E (1993) 5-hydroxytryptamine1C receptor density and mRNA levels in choroid plexus epithelial cells after treatment with mianserin and (−)-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane. Mol Pharmacol 44:725–730PubMedGoogle Scholar
  9. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedCrossRefGoogle Scholar
  10. Berendsen HH, Broekkamp CL (1991) Attenuation of 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour in rats following chronic treatment with 5-HT receptor agonists, antagonists or anti-depressants. Psychopharmacology 105:219–224PubMedCrossRefGoogle Scholar
  11. Bristow LJ, O’Connor D, Watts R, Duxon MS, Hutson PH (2000) Evidence for accelerated desensitisation of 5-HT(2C) receptors following combined treatment with fluoxetine and the 5-HT(1A) receptor antagonist, WAY 100,635, in the rat. Neuropharmacology 39:1222–1236PubMedCrossRefGoogle Scholar
  12. Chanrion B, Mannoury la Cour C, Gavarini S et al (2008) Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulation of cell surface expression and signal transduction. Mol Pharmacol 73:748–757. doi: 10.1124/mol.107.041574 PubMedCrossRefGoogle Scholar
  13. Clemett DA, Punhani T, Duxon MS, Blackburn TP, Fone KC (2000) Immunohistochemical localisation of the 5-HT2C receptor protein in the rat CNS. Neuropharmacology 39:123–132PubMedCrossRefGoogle Scholar
  14. De Deurwaerdere P, Navailles S, Berg KA, Clarke WP, Spampinato U (2004) Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci 24:3235–3241. doi: 10.1523/JNEUROSCI.0112-04.2004 PubMedCrossRefGoogle Scholar
  15. Dekeyne A, Denorme B, Monneyron S, Millan MJ (2000) Citalopram reduces social interaction in rats by activation of serotonin (5-HT)(2C) receptors. Neuropharmacology 39:1114–1117PubMedCrossRefGoogle Scholar
  16. Di Giovanni G, Di Matteo V, La Grutta V, Esposito E (2001) m-Chlorophenylpiperazine excites non-dopaminergic neurons in the rat substantia nigra and ventral tegmental area by activating serotonin-2C receptors. Neuroscience 103:111–116PubMedCrossRefGoogle Scholar
  17. Di Giovanni G, Di Matteo V, Pierucci M, Benigno A, Esposito E (2006) Serotonin involvement in the basal ganglia pathophysiology: could the 5-HT2C receptor be a new target for therapeutic strategies? Curr Med Chem 13:3069–3081. doi: 10.1523/JNEUROSCI.3895-04.2005 PubMedCrossRefGoogle Scholar
  18. 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 26:246–258. doi: 10.1016/S0893-133X(01)00314-1 PubMedCrossRefGoogle Scholar
  19. 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 261:89–92PubMedCrossRefGoogle Scholar
  20. Fogel SM, Smith CT, Beninger RJ (2009) Evidence for 2-stage models of sleep and memory: learning-dependent changes in spindles and theta in rats. Brain Res Bull 79:445–451. doi: 10.1016/j.brainresbull.2009.03.002 PubMedCrossRefGoogle Scholar
  21. Fone KC, Austin RH, Topham IA, Kennett GA, Punhani T (1998) Effect of chronic m-CPP on locomotion, hypophagia, plasma corticosterone and 5-HT2C receptor levels in the rat. Br J Pharmacol 123:1707–1715. doi: 10.1038/sj.bjp.0701798 PubMedCrossRefGoogle Scholar
  22. Frank MG, Stryker MP, Tecott LH (2002) Sleep and sleep homeostasis in mice lacking the 5-HT2c receptor. Neuropsychopharmacology 27:869–873. doi: 10.1016/S0893-133X(02)00353-6 PubMedCentralPubMedCrossRefGoogle Scholar
  23. Gandolfo G, Scherschlicht R, Gottesmann C (1994) Benzodiazepines promote the intermediate stage at the expense of paradoxical sleep in the rat. Pharmacol Biochem Behav 49:921–927PubMedCrossRefGoogle Scholar
  24. 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 359:45–48. doi: 10.1016/j.neulet.2004.01.072 PubMedCrossRefGoogle Scholar
  25. Hajos M, Hoffmann WE, Weaver RJ (2003) Regulation of septo-hippocampal activity by 5-hydroxytryptamine(2C) receptors. J Pharmacol Exp Ther 306:605–615. doi: 10.1124/jpet.103.051169 PubMedCrossRefGoogle Scholar
  26. Hrdina PD, Vu TB (1993) Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT2 receptors in rat brain: an autoradiographic study. Synapse 14:324–331. doi: 10.1002/syn.890140410 PubMedCrossRefGoogle Scholar
  27. Huber R, Deboer T, Schwierin B, Tobler I (1998) Effect of melatonin on sleep and brain temperature in the Djungarian hamster and the rat. Physiol Behav 65:77–82PubMedCrossRefGoogle Scholar
  28. Jensen NH, Cremers TI, Sotty F (2010) Therapeutic potential of 5-HT2C receptor ligands. Sci World J 10:1870–1885. doi: 10.1100/tsw.2010.180 CrossRefGoogle Scholar
  29. Kantor S, Anheuer ZE, Bagdy G (2000) High social anxiety and low aggression in Fawn-Hooded rats. Physiol Behav 71:551–557PubMedCrossRefGoogle Scholar
  30. 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 943:105–111PubMedCrossRefGoogle Scholar
  31. 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 142:1332–1342. doi: 10.1038/sj.bjp.0705887 PubMedCrossRefGoogle Scholar
  32. 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 315:921–930. doi: 10.1124/jpet.105.086413 PubMedCrossRefGoogle Scholar
  33. Kennedy AJ, Gibson EL, O’Connell MT, Curzon G (1993) Effects of housing, restraint and chronic treatments with mCPP and sertraline on behavioural responses to mCPP. Psychopharmacology 113:262–268PubMedCrossRefGoogle Scholar
  34. Kennett GA, Wood MD, Bright F et al (1997) SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36:609–620PubMedCrossRefGoogle Scholar
  35. Kitka T, Bagdy G (2008) Effect of 5-HT2A/2B/2C receptor agonists and antagonists on sleep and waking in laboratory animals and humans. In: Monti JM, Jacobs BL, Nutt DJ (eds) Serotonin and sleep: molecular, functional and clinical aspects. Birkhäuser, Basel, pp 387–414CrossRefGoogle Scholar
  36. Lader M, Andersen HF, Baekdal T (2005) The effect of escitalopram on sleep problems in depressed patients. Hum Psychopharmacol 20:349–354. doi: 10.1002/hup.694 PubMedCrossRefGoogle Scholar
  37. Leysen JE (2004) 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord 3:11–26PubMedCrossRefGoogle Scholar
  38. Li Q, Brownfield MS, Battaglia G, Cabrera TM, Levy AD, Rittenhouse PA, van de Kar LD (1993) Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). J Pharmacol Exp Ther 266:836–844PubMedGoogle Scholar
  39. Martin JR, Bos M, Jenck F et al (1998) 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 286:913–924PubMedGoogle Scholar
  40. Mendelson WB (1996) Sleep induction by microinjection of pentobarbital into the medial preoptic area in rats. Life Sci 59:1821–1828PubMedCrossRefGoogle Scholar
  41. 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 28:850–856. doi: 10.1038/sj.npp.1300109 PubMedGoogle Scholar
  42. Monti JM, Jantos H (1992) Dose-dependent effects of the 5-HT1A receptor agonist 8-OH-DPAT on sleep and wakefulness in the rat. J Sleep Res 1:169–175PubMedCrossRefGoogle Scholar
  43. Monti JM, Jantos H (2006a) Effects of activation and blockade of 5-HT2A/2C receptors in the dorsal raphe nucleus on sleep and waking in the rat. Prog Neuropsychopharmacol Biol Psychiatry 30:1189–1195. doi: 10.1016/j.pnpbp.2006.02.013 PubMedCrossRefGoogle Scholar
  44. Monti JM, Jantos H (2006b) Effects of the serotonin 5-HT2A/2C receptor agonist DOI and of the selective 5-HT2A or 5-HT2C receptor antagonists EMD 281014 and SB-243213, respectively, on sleep and waking in the rat. Eur J Pharmacol 553:163–170. doi: 10.1016/j.ejphar.2006.09.027 PubMedCrossRefGoogle Scholar
  45. Newton RA, Elliott JM (1997) Mianserin-induced down-regulation of human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors stably expressed in the human neuroblastoma cell line SH-SY5Y. J Neurochem 69:1031–1038PubMedCrossRefGoogle Scholar
  46. Owens MJ, Knight DL, Nemeroff CB (2001) Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry 50:345–350PubMedCrossRefGoogle Scholar
  47. Pompeiano M, Palacios JM, Mengod G (1994) Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Brain Res Mol Brain Res 23:163–178PubMedCrossRefGoogle Scholar
  48. Popa D, Lena C, Fabre V et al (2005) Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci 25:11231–11238. doi: 10.1523/JNEUROSCI.1724-05.2005 PubMedCrossRefGoogle Scholar
  49. Pranzatelli MR, Tailor PT (1994) Modulation of brainstem 5-HT1C receptors by serotonergic drugs in the rat. Gen Pharmacol 25:1279–1284PubMedCrossRefGoogle Scholar
  50. Pranzatelli MR, Murthy JN, Tailor PT (1993) Novel regulation of 5-HT1C receptors: down-regulation induced both by 5-HT1C/2 receptor agonists and antagonists. Eur J Pharmacol 244:1–5PubMedCrossRefGoogle Scholar
  51. Prisco S, Esposito E (1995) Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area. Br J Pharmacol 116:1923–1931PubMedCrossRefGoogle Scholar
  52. Rush AJ, Armitage R, Gillin JC et al (1998) Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder. Biol Psychiatry 44:3–14PubMedCrossRefGoogle Scholar
  53. Rutter JJ, Gundlah C, Auerbach SB (1994) Increase in extracellular serotonin produced by uptake inhibitors is enhanced after chronic treatment with fluoxetine. Neurosci Lett 171:183–186PubMedCrossRefGoogle Scholar
  54. Schlag BD, Lou Z, Fennell M, Dunlop J (2004) Ligand dependency of 5-hydroxytryptamine 2C receptor internalization. J Pharmacol Exp Ther 310:865–870. doi: 10.1124/jpet.104.067306 PubMedCrossRefGoogle Scholar
  55. Serrats J, Mengod G, Cortes R (2005) Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei. J Chem Neuroanat 29:83–91. doi: 10.1016/j.jchemneu.2004.03.010 PubMedCrossRefGoogle Scholar
  56. Serretti A, Artioli P, De Ronchi D (2004) The 5-HT2C receptor as a target for mood disorders. Expert Opin Ther Targets 8:15–23. doi: 10.1517/14728222.8.1.15 PubMedCrossRefGoogle Scholar
  57. 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 126:50–54PubMedCrossRefGoogle Scholar
  58. Smith MI, Piper DC, Duxon MS, Upton N (2002) Effect of SB-243213, a selective 5-HT(2C) receptor antagonist, on the rat sleep profile: a comparison to paroxetine. Pharmacol Biochem Behav 71:599–605PubMedCrossRefGoogle Scholar
  59. Sorman E, Wang D, Hajos M, Kocsis B (2011) Control of hippocampal theta rhythm by serotonin: role of 5-HT2c receptors. Neuropharmacology. doi: 10.1016/j.neuropharm.2011.01.029 PubMedCentralPubMedGoogle Scholar
  60. Steiger A, Kimura M (2009) Wake and sleep EEG provide biomarkers in depression. J Psychiatr Res. doi: 10.1016/j.jpsychires.2009.08.013 Google Scholar
  61. To CT, Bagdy G (1999) Anxiogenic effect of central CCK administration is attenuated by chronic fluoxetine or ipsapirone treatment. Neuropharmacology 38:279–282PubMedCrossRefGoogle Scholar
  62. To CT, Anheuer ZE, Bagdy G (1999) Effects of acute and chronic fluoxetine treatment of CRH-induced anxiety. NeuroReport 10:553–555PubMedCrossRefGoogle Scholar
  63. Tortella FC, Echevarria E, Pastel RH, Cox B, Blackburn TP (1989) Suppressant effects of selective 5-HT2 antagonists on rapid eye movement sleep in rats. Brain Res 485:294–300PubMedCrossRefGoogle Scholar
  64. Trouvin JH, Gardier AM, Chanut E, Pages N, Jacquot C (1993) Time course of brain serotonin metabolism after cessation of long-term fluoxetine treatment in the rat. Life Sci 52:PL187–PL192PubMedCrossRefGoogle Scholar
  65. Ulrichsen J, Partilla JS, Dax EM (1992) Long-term administration of m-chlorophenylpiperazine (mCPP) to rats induces changes in serotonin receptor binding, dopamine levels and locomotor activity without altering prolactin and corticosterone secretion. Psychopharmacology 107:229–235PubMedCrossRefGoogle Scholar
  66. Urbain N, Creamer K, Debonnel G (2006) Electrophysiological diversity of the dorsal raphe cells across the sleep-wake cycle of the rat. J Physiol 573:679–695. doi: 10.1113/jphysiol.2006.108514 PubMedCrossRefGoogle Scholar
  67. Vas S, Katai Z, Kostyalik D et al (2013) Differential adaptation of REM sleep latency, intermediate stage and theta power effects of escitalopram after chronic treatment. J Neural Transm 120:169–176. doi: 10.1007/s00702-012-0847-2 PubMedCrossRefGoogle Scholar
  68. Vertes RP, Kocsis B (1997) Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience 81:893–926PubMedCrossRefGoogle Scholar
  69. Wilson S, Argyropoulos S (2005) Antidepressants and sleep: a qualitative review of the literature. Drugs 65:927–947PubMedCrossRefGoogle Scholar
  70. 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 14:367–372. doi: 10.1016/j.euroneuro.2003.11.004 PubMedCrossRefGoogle Scholar
  71. Yamauchi M, Tatebayashi T, Nagase K, Kojima M, Imanishi T (2004) Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats. Pharmacol Biochem Behav 78:683–689. doi: 10.1016/j.pbb.2004.05.003 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Diána Kostyalik
    • 1
  • Zita Kátai
    • 1
  • Szilvia Vas
    • 1
    • 2
  • Dorottya Pap
    • 1
    • 2
  • Péter Petschner
    • 1
    • 2
  • Eszter Molnár
    • 1
  • István Gyertyán
    • 3
  • Lajos Kalmár
    • 4
  • László Tóthfalusi
    • 1
  • Gyorgy Bagdy
    • 1
    • 2
    Email author
  1. 1.Department of PharmacodynamicsSemmelweis UniversityBudapestHungary
  2. 2.MTA-SE, Neuropsychopharmacology and Neurochemistry Research GroupBudapestHungary
  3. 3.Department of Behavioural PharmacologyGedeon Richter Plc.BudapestHungary
  4. 4.Institute of Enzymology, Research Centre for Natural SciencesHungarian Academy of SciencesBudapestHungary

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