Skip to main content
SpringerLink
Log in

Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep–wake cycle architecture

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 05 May 2009

Abstract

Rationale

The novel antidepressant, agomelatine, behaves as an agonist at melatonin MT1 and MT2 receptors and as an antagonist at serotonin (5-HT)2C receptors. In animal models and clinical trials, agomelatine displays antidepressant properties and re-synchronizes disrupted circadian rhythms.

Objectives

The objectives of this study were to compare the influence of agomelatine upon sleep–wake states to the selective melatonin agonists, melatonin and ramelteon, and to the selective 5-HT2C receptor antagonist, S32006.

Methods

Rats were administered with vehicle, agomelatine, ramelteon, melatonin, or S32006, at the onset of either dark or light periods. Polygraphic recordings were performed and changes determined over 24 h, i.e., number and duration of sleep–wake episodes, latencies to rapid eye movement (REM) and slow-wave (SWS) sleep, power band spectra of the electroencephalogram (EEG), and circadian changes.

Results

Administered at light phase onset, no changes were induced by agomelatine. In contrast, administered shortly before dark phase, agomelatine (10 and 40 mg/kg, per os) enhanced duration of REM and SWS sleep and decreased wake state for 3 h. Melatonin (10 mg/kg, per os) induced a transient enhancement in REM sleep followed by a reduction in REM and SWS sleep and an increase in waking. Ramelteon (10 mg/kg, per os) provoked a transient increase in REM sleep. Finally, S32006 (10 mg/kg, intraperitoneally), administered at dark phase onset, mimicked the increased SWS provoked by agomelatine, yet diminished REM sleep.

Conclusions

Agomelatine possesses a distinctive EEG profile compared with melatonin, ramelteon, and S32006, possibly reflecting co-joint agonist and antagonist properties at MT1/MT2 and 5-HT2C receptors, respectively.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Armstrong SM, McNulty OM, Guardiola-Lemaître B, Redman JR (1993) Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS). Pharmacol Biochem Behav 46:45–49

    Article  PubMed  CAS  Google Scholar 

  • Aston-Jones G, Chen S, Zhu Y, Oshinsky ML (2001) A neural circuit for circadian regulation of arousal. Nat Neurosci 4:732–738

    Article  PubMed  CAS  Google Scholar 

  • Audinot V, Mailliet F, Lahaye-Brasseur C, Bonnaud A, Le Gall A, Amosse C, Dromaint S, Rodriguez M, Nagel N, Galizzi JP, Malpaux B, Guillaumet G, Lesieur D, Lefoulon F, Renard P, Delagrange P, Boutin JA (2003) New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 367:553–561

    Article  CAS  Google Scholar 

  • Austin MP, Mitchell P, Goodwin GM (2001) Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry 178:200–206

    Article  PubMed  CAS  Google Scholar 

  • Baskett JJ, Broad JB, Wood PC, Duncan JR, Pledger MJ, English J, Arendt J (2003) Does melatonin improve sleep in older people? A randomized crossover trial. Age Ageing 32:164–170

    Article  PubMed  Google Scholar 

  • Bertaina-Anglade V, La Rochelle CD, Boyer PA, Mocaer E (2006) Antidepressant-like effect of agomelatine in the learned helplessness model. Behav Pharmacol 17:703–713

    Article  PubMed  CAS  Google Scholar 

  • Borja N, Daniel KL (2006) Ramelteon for the treatment of insomnia. Clin Therapeutics 28:1540–1555

    Article  CAS  Google Scholar 

  • Bourin M, Mocaër E, Porsolt R (2004) Antidepressant-like activity of S 20098 in the forced swimming test in rodents. Involvement of melatonin and 5-HT receptors. J Psy Neurosci 29:126–133

    Google Scholar 

  • Cajochen C, Krauchi K, Graw P, Wirz-Justice A (1997) Melatonin and S-20098 increase REM sleep and wake-up propensity without modifying NREM sleep homeostasis. Am J Physiol 272:1189–1196

    Google Scholar 

  • Cajochen C, Kräuchi K, Wirz-Justice A (2003) Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol 15:432–437

    Article  PubMed  CAS  Google Scholar 

  • Cespuglio R, Marinesco S, Baubet V, El Kafi B (1995) Evidence for a sleep-promoting influence of stress. Adv Neuroimmunol 5:145–154

    Article  PubMed  CAS  Google Scholar 

  • Cespuglio R, Rousset C, Debilly G, Rochat C, Millan MJ (2005) Acute administration of the novel serotonin and noradrenaline reuptake inhibitor, S33005, markedly modifies sleep–wake cycle architecture in the rat. Psychopharmacology (Berl) 181:639–652

    Article  CAS  Google Scholar 

  • Chagraoui A, Protais P, Filloux T, Mocaër E (2003) Agomelatine (S20098) antagonizes the penile erections induced by the stimulation of 5-HT2C receptors in Wistar rats. Psychopharmacology (Berl) 170:17–22

    Article  CAS  Google Scholar 

  • Clement P, Gharib A, Cespuglio R, Sarda N (2003) Changes in sleep–wake cycle architecture and cortical NO release during aging in the rat. Neuroscience 116:863–870

    Article  PubMed  CAS  Google Scholar 

  • Corbach S, Schmelting B, Fuchs E, Mocaër E (2007) Comparison of agomelatine and melatonin for effects in chronically stressed tree shrews, an animal model of depression. Eur Neurophyschopharmacol 17:S364

    Article  Google Scholar 

  • Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM (2000) Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci 25:48–52

    PubMed  CAS  Google Scholar 

  • De Deurwaerdère P, Navaille 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

    Article  PubMed  CAS  Google Scholar 

  • Dekeyne A, Mannoury La Cour C, Gobert A, Brocco M, Lejeune F, Serres F, Sharp T, Daszuta A, Soumier A, Papp M, Rivet JM, Flik G, Cremers TI, Muller O, Lavielle G, Millan MJ (2008) S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology (Berl) 199(4):549–568

    Article  CAS  Google Scholar 

  • Dugovic C, Leysen JE, Wauquier A (1989a) Melatonin modulates the sensitivity of 5-hydroxytryptamine-2 receptor-mediated sleep–wakefulness regulation in the rat. Neurosci Lett 104:320–325

    Article  PubMed  CAS  Google Scholar 

  • Dugovic C, Wauquier A, Leysen JE, Marrannes R, Jannsen PA (1989b) Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat. Psychopharmacology (Berl) 97:436–442

    Article  CAS  Google Scholar 

  • Erman M, Seiden D, Zammit G, Sainati S, Zhang J (2006) An efficacy, safety and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep 7:17–24

    Article  Google Scholar 

  • Fu CH, Williams SC, Brammer MJ, Suckling J, Kim J, Cleare AJ, Walsh ND, Mitterschiffthaler MT, Andrew CM, Pich EM, Bullmore ET (2007) Neural responses to happy facial expressions in major depression following antidepressant treatment. Am J Psychiatry 164:599–607

    Article  PubMed  Google Scholar 

  • Gibbs FP, Uriend J (1981) The half life of melatonin elimination from rat plasma. Endocrinology 109:1796–1798

    Article  PubMed  CAS  Google Scholar 

  • Gorka Z, Moryl E, Papp M (1996) Effect of chronic mild stress on circadian rhythms in the locomotor activity in rats. Pharmacol Biochem Behav 54:229–234

    Article  PubMed  CAS  Google Scholar 

  • Grassi-Zucconi G, Semprevivo M, Mocaer E, Kristensson K, Bentivoglio M (1996) Melatonin and its new antagonist S-20098 restore synchronized sleep fragmented by experimental trypanosome infection in the rat. Brain Res Bull 39:63–68

    Article  PubMed  CAS  Google Scholar 

  • Hack LM, Lockley SW, Arendt J, Skene DJ (2003) The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. J Biol Rhythms 18:420–429

    Article  PubMed  CAS  Google Scholar 

  • Holmes MC, French KL, Seckl JR (1997) Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid gene expression in the hippocampus with food restriction and glucocorticoids. J Neurosci 17:4056–4065

    PubMed  CAS  Google Scholar 

  • 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 65:77–82

    Article  PubMed  CAS  Google Scholar 

  • Hughes RJ, Sack RL, Lewy AJ (1998) The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep 21:52–68

    PubMed  CAS  Google Scholar 

  • Ishikawa A, Kanayama Y, Matsumura H, Tsuchimochi H, Ishida Y, Nakamura S (2006) Selective rapid eye movement sleep deprivation impairs the maintenance of long-term potentiation in the rat hippocampus. Eur J Neurosci 24:243–248

    Article  PubMed  Google 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 943:105–111

    Article  PubMed  CAS  Google Scholar 

  • Karim A, Tolbert D, Cao C (2006) Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol 46(2):140–148

    Article  PubMed  CAS  Google Scholar 

  • Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M (2005) Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology 48:301–310

    Article  PubMed  CAS  Google Scholar 

  • Kennedy SH, Emsley R (2006) Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol 16:93–100

    Article  PubMed  CAS  Google Scholar 

  • Lemoine P, Guilleminault C, Alvarez E (2007) Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry 68:1723–1732

    Article  PubMed  CAS  Google Scholar 

  • Leproult R, Van Onderbergen A, L’Hermite-Baleriaux M, Van Cauter E, Copinschi G (2005) Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf) 63:298–304

    Article  CAS  Google Scholar 

  • Lewy AJ, Ahmed S, Jackson JM, Sack RL (1992) Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 9:380–392

    Article  PubMed  CAS  Google Scholar 

  • Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J (2000) Melatonin administration can entrain the free-running circadian system in blind subjects. J Endocrinol 164:R1–R6

    Article  PubMed  CAS  Google Scholar 

  • Lucassen PJ, Heine VM, Muller MB, van der Beek EM, Wiegant VM, De Kloet ER, Joels M, Fuchs E, Swaab DF, Czeh B (2006) Stress, depression and hippocampal apoptosis. CNS Neurol Disord Drug Targets 5:531–546

    Article  PubMed  Google Scholar 

  • Mahlberg R, Kunz D (2007) Melatonin excretion levels and polysomnographic sleep parameters in healthy subjects and patients with sleep-related disturbances. Sleep Med 8:512–516

    Article  PubMed  Google Scholar 

  • Marinesco S, Bonnet C, Cespuglio R (1999) Influence of stress duration on the sleep rebound induced by immobilization in the rat: a possible role for corticosterone. Neuroscience 92:921–933

    Article  PubMed  CAS  Google Scholar 

  • Martinet L, Guardiola-Lemaître B, Mocaër E (1996) Rhythms by S 20098, a melatonin agonist, is dose and plasma concentration dependent. Pharmacol Biochem Behav 54:713–718

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ (2005) Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie 60:441–460

    Article  PubMed  Google Scholar 

  • Millan MJ (2006) Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther 110:135–370

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ, Lejeune F, Gobert A (2000) Reciprocal autoreceptor and heteroreceptor control of serotoninergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents. J Psychopharmacol 14:114–138

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D (2003) The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther 306:954–64

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ, Brocco M, Gobert A, Dekeyne A (2005) Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2c receptors blockade. Psychopharmacology (Berl) 177:448–458

    Article  CAS  Google Scholar 

  • Miyamoto M, Nishikawa H, Doken Y, Hirai K, Uchikawa O, Ohkawa S (2004) The sleep-promoting action of ramelteon (TAK-375) in freely moving cats. Sleep 27(7):1319–1325

    PubMed  Google Scholar 

  • Monti JM, Jantos H (2006) 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

    Article  PubMed  CAS  Google Scholar 

  • Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC (2005) Phase-dependent treatment of delayed sleep phase syndrome with melatonin. Sleep 28(10):1214–1216

    Google Scholar 

  • Olié JP, Kasper S (2007) Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol 10:661–673

    PubMed  Google Scholar 

  • Pandi-Perumal SR, Srinivasan V, Poeggeler B, Hardeland R, Cardinali DP (2007) Drug insight: the use of melatoninergic agonists for the treatment of insomnia-focus on ramelteon. Nat Clin Pract Neurol 3:221–228

    Article  PubMed  CAS  Google Scholar 

  • Papp M, Gruca P, Boyer P-A, Mocaer E (2003) Effect of agomelatine in the chronic mild stress model of depression in the rat. Neuropsychopharmacology 28:694–703

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Quera Salva MA, Vanier B, Laredo J, Hartley S, Chapotot F, Moulin C, Lofaso F, Guilleminault C (2007) Major depressive disorder, sleep EEG and agomelatine: an open-label study. Int J Neuropsychopharmacol 10:691–696

    PubMed  CAS  Google Scholar 

  • Rajaratnam SM, Dijk DJ, Middleton B, Stone BM, Arendt J (2003) Melatonin phase-shifts human circadian rhythms with no evidence of changes in the duration or endogenous melatonin secretion or the 24-hour production of reproductive hormones. J Clin Endocrinol Metab 88:4303–4309

    Article  PubMed  CAS  Google Scholar 

  • Redman JR, Francis AJP (1998) Entrainment of rat circadian rhythms by the melatonin agonist S 20098 requires intact suprachiasmatic nuclei but not the pineal. J Biological Rhythms 13:39–51

    Article  CAS  Google Scholar 

  • Redman JR, Guardiola-Lemaître B, Brown M, Delagrange P, Armstrong SM (1995) Dose-dependent effects of S 20098, a melatonin agonist, on direction of re-entrainment of rat circadian activity rhythms. Psychopharmacology (Berl) 118:385–390

    Article  CAS  Google Scholar 

  • Rijnbeek B, de Visser SJ, Franson KL, Cohen AF, van Gerven JM (2003) REM sleep effects as a biomarker for the effects of antidepressants in healthy volunteers. J Psychopharmacol 17:196–203

    Article  PubMed  CAS  Google Scholar 

  • Roth T, Stubbs C, Walsh JK (2005) Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep 28:303–307

    PubMed  Google Scholar 

  • Schittecatte M, Dumont F, Machowski R, Cornil C, Lavergne F, Wilmotte J (2002) Effects of mirtazapine on sleep polygraphic variables in major depression. Neuropsychobiology 46:197–201

    Article  PubMed  CAS  Google Scholar 

  • Sharpley AI, Cowen PJ (1995) Effect of pharmacologic treatments on the sleep of depressed patients. Biol Psychiatry 37:85–98

    Article  PubMed  CAS  Google Scholar 

  • Sharpley AL, Elliott JM, Attenburrw MJ, Cowen PJ (1994) Slow wave sleep in humans: role of 5-HT2A and 5-HT2C receptors. Neuropharmacology 33:467–471

    Article  PubMed  CAS  Google Scholar 

  • Slotten HA, Krekling S, Sicard B, Pévet P (2002) Daily infusion of melatonin entrains circadian activity rhythms in the diurnal rodent Arvicanthis ansorgei. Behav Brain Res 133:11–19

    Article  PubMed  CAS  Google Scholar 

  • Smith MI, Piper DC, Duxon MS, Upton N (2002) Effect of SB-243213, a selective 5HT2c receptor antagonist on the rat sleep profile: a comparison to paroxetine. Pharmacol Biochem Behav 71:599–605

    Article  PubMed  CAS  Google Scholar 

  • Tobler I, Jaggi K, Borbely AA (1994) Effects of melatonin and the melatonin receptor agonist S-20098 on the vigilance states, EEG spectra and cortical temperature in the rat. J Pineal Res 16:26–32

    Article  PubMed  CAS  Google Scholar 

  • Trivedi MH, Rush AJ, Armitage R, Gullion CM, Grannemann BD, Orsulak PJ, Roffwarg HP (1999) Effects of fluoxetine on polysomnogram in outpatients with major depression. Neuropsychopharmacology 20:447–59

    Article  PubMed  CAS  Google Scholar 

  • Ursin R (2002) Serotonin and sleep. Sleep Med Rev 6:57–69

    Article  Google Scholar 

  • Van Reeth O, Olivares E, Zhang Y, Zee PC, Mocaer E, Defrance R, Turek FW (1997) Comparative effects of a melatonin agonist on the circadian system in mice and Syrian hamsters. Brain Res 762(1–2):185–194

    PubMed  Google Scholar 

  • Vogel GW, Buffenstein A, Minter K, Hennessey A (1990) Drug effects on REM sleep and on endogenous depression. Neurosci Biobehav Rev 14:49–63

    Article  PubMed  CAS  Google Scholar 

  • Wade AG, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, Zisapel N (2007) Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin 23:2597–2605

    Article  PubMed  CAS  Google Scholar 

  • Winokur A, Gary KA, Rodner S, Rae-Red C, Fernando AT, Szuba MP (2001) Depression, sleep physiology, and antidepressant drugs. Depress Anxiety 14:19–28

    Article  PubMed  CAS  Google Scholar 

  • Wirz-Justice A, Van den Hoofdakker RH (1999) Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry 15:445–453

    Article  Google Scholar 

  • Zemlan FP, Mulchahey JJ, Scharf MB, Mayleben DW, Rosenberg R, Lankford A (2005) The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial. J Clin Psychiatry 66:384–390

    Article  PubMed  CAS  Google Scholar 

  • Zupancic M, Guilleminault C (2006) Agomelatine: a preliminary review of a new antidepressant. CNS Drugs 20:981–992

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Claude Bernard University, Lyon, EA4170, France

    Amandine Descamps, Colette Rousset & Raymond Cespuglio

  2. Department of Psychopharmacology, Institut de Recherches Internationales Servier, Neuilly-sur-Seine, France

    Mark Millan

  3. Experimental Sciences Department, Institut de Recherches Internationales Servier, Neuilly-sur-Seine, France

    Michael Spedding & Philippe Delagrange

Authors
  1. Amandine Descamps
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Colette Rousset
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark Millan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Spedding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Philippe Delagrange
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Raymond Cespuglio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amandine Descamps.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-009-1556-x

Rights and permissions

Reprints and permissions

About this article

Cite this article

Descamps, A., Rousset, C., Millan, M. et al. Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep–wake cycle architecture. Psychopharmacology 205, 93–106 (2009). https://doi.org/10.1007/s00213-009-1519-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1519-2

Keywords

Search

Navigation