, Volume 177, Issue 4, pp 448–458 | Cite as

Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade

  • Mark J. MillanEmail author
  • Mauricette Brocco
  • Alain Gobert
  • Anne Dekeyne
Original Investigation



The novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors and as an antagonist at serotonin (5-HT)2C receptors.


To determine whether, by virtue of its antagonist properties at 5-HT2C receptors, agomelatine elicits anxiolytic properties in rats.


Employing a combined neurochemical and behavioural approach, actions of agomelatine were compared to those of melatonin, the selective 5-HT2C receptor antagonist, SB243,213, and the benzodiazepine, clorazepate.


In unfamiliar pairs of rats exposed to a novel environment, agomelatine enhanced the time devoted to active social interaction, an action mimicked by clorazepate and by SB243,213. In a Vogel conflict procedure, agomelatine likewise displayed dose-dependent anxiolytic activity with a maximal effect comparable to clorazepate, and SB243,213 was similarly active in this procedure. In a plus-maze procedure in which clorazepate significantly enhanced percentage entries into open arms, agomelatine revealed only modest activity and SB243,213 was inactive. Further, like SB243,213, and in contrast to clorazepate, agomelatine did not suppress ultrasonic vocalizations emitted by rats re-exposed to an environment associated with an aversive stimulus. Whereas clorazepate reduced dialysate levels of 5-HT and noradrenaline in hippocampus and frontal cortex of freely moving rats, agomelatine did not affect extracellular levels of 5-HT and elevated those of noradrenaline. SB243,213 acted similarly to agomelatine. Melatonin, which did not modify extracellular levels of 5-HT or noradrenaline, was ineffective in all models of anxiolytic activity. Furthermore, the selective melatonin antagonist, S22153, did not modify anxiolytic properties of agomelatine in either the social interaction or the Vogel Conflict tests.


In contrast to melatonin, and reflecting blockade of 5-HT2C receptors, agomelatine is active in several models of anxiolytic properties in rodents. The anxiolytic profile of agomelatine differs from that of benzodiazepines from which it may also be distinguished by its contrasting influence on corticolimbic monoaminergic pathways.


Melatonin 5-HT2C receptors Anxiety Anxiolytic Conflict Frontal cortex Dorsal hippocampus 



The authors thank Laetitia Cistarelli, Brigitte Denorme, Huguette Gressier, Loretta Iob, Rodolphe Billiras, Christophe Melon and Jimmy Mullot for technical assistance, and Marianne Soubeyran for secretarial assistance. E. Mocäer is thanked for helpful comments on the manuscript.


  1. Atsmon J, Oaknin S, Laudon M, Laschiner S, Gavish M, Dagan Y, Zisapel N (1996) Reciprocal effects of chronic diazepam and melatonin on brain melatonin and benzodiazepine binding sites. J Pineal Res 20:65–71PubMedGoogle Scholar
  2. Belzung C (2001) The genetic basis of the pharmacological effects of anxiolytics: a review based on rodent models. Behav Pharmacol 12:451–460PubMedGoogle Scholar
  3. Borjigin J, Li X, Snyder SH (1999) The pineal gland and melatonin: molecular and pharmacologic regulation. Annu Rev Pharmacol Toxicol 39:53–65CrossRefPubMedGoogle Scholar
  4. Bristow LJ, O’Connor D, Watts R, Duxon MS, Hutson PH (2000) Evidence for accelerated desensitisation of 5-HT2C receptors following combined treatment with fluoxetine and the 5-HT1A receptor antagonist, WAY100,635, in the rat. Neuropharmacology 39:1222–1236CrossRefPubMedGoogle Scholar
  5. Cardinali DP, Gvozdenovich E, Kaplan MR, Fainstein I, Shifis HA, Pérez Lloret S, Albornoz L, Negri A (2002) A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly. Neuroendocrinol Lett 23:55–60Google Scholar
  6. Casacalenda N, Boulenger JP (1998) Pharmacologic treatment effective in both generalized anxiety disorder and major depressive disorder: clinical and theoretical implications. Can J Psychiatry 43:722–730PubMedGoogle Scholar
  7. Cervo L, Samanin R (1995) 5-HT1A receptor full and partial agonists and 5-HT1C (but not 5-HT3) receptor antagonists increase rates of punished responding in rats. Pharmacol Biochem Behav 52:671–676CrossRefPubMedGoogle Scholar
  8. 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 170:17–22Google Scholar
  9. Chuang IL, Lin MT (1994) Pharmacological effects of melatonin treatment on both locomotor activity and brain serotonin release in rats. J Pineal Res 17:11–16PubMedGoogle Scholar
  10. Clemett DA, Punhani T, Duxon MS, Blackburn TP, Fone KCF (2000) Immunohistochemical localisation of the 5-HT2C receptor protein in the rat CNS. Neuropharmacology 39:123–132CrossRefPubMedGoogle Scholar
  11. Clément Y, Calatayud F, Belzung C (2002) Genetic basis of anxiety-like behaviour: a critical review. Brain Res Bull 57:57–71CrossRefPubMedGoogle Scholar
  12. Das S, Tecott L (1996) Diminished anxiety-like responses in 5-HT2C receptor mutant mice. Soc Neurosci Abstr 22:811–812Google Scholar
  13. Deakin JFW (1994) Three distinct roles of 5-HT in anxiety, panic and depression. In: Montgomery SA, Corn TH (eds) Psychopharmacology of depression. British Association for Psychopharmacology, Cambridge, vol 13, pp 87–101Google Scholar
  14. Dekeyne A, Brocco M, Adhumeau A, Gobert A, Millan MJ (2000a) The selective serotonin 5-HT1A receptor ligand, S15535, displays anxiolytic-like effects in the social interaction and Vogel models and suppresses dialysate levels of 5-HT in the dorsal hippocampus of freely-moving rats: a comparison with other anxiolytic agents. Psychopharmacology 152:55–66Google Scholar
  15. Dekeyne A, Denorme B, Monneyron S, Millan MJ (2000b) Citalopram reduces social interaction in rats by activation of serotonin (5-HT)2C receptors. Neuropharmacology 39:1114–1117CrossRefPubMedGoogle Scholar
  16. File SE, Seth P (2003) A review of 25 years of the social interaction test. Eur J Pharmacol 463:35–53CrossRefPubMedGoogle Scholar
  17. Foote SL, Aston-Jones GS (1995) Pharmacology and physiology of central noradrenergic systems. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation in progress. Raven, New York, pp 347–354Google Scholar
  18. Gobert A, Rivet J-M, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas J-P, Cistarelli L, Melon C, Millan MJ (2000) Serotonin2C receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221CrossRefPubMedGoogle Scholar
  19. Golombek DA, Martini M, Cardinali DP (1993) Melatonin as an anxiolytic in rats: time dependence and interaction with the central GABAergic system. Eur J Pharmacol 237:231–236CrossRefPubMedGoogle Scholar
  20. Golombek DA, Pevet P, Cardinali DP (1996) Melatonin effects on behavior: possible mediation by the central GABAergic system. Neurosci Biobehav Res 20:403–412CrossRefGoogle Scholar
  21. Gorman JM, Kent JM, Sullivan GM, Coplan JD (2000) Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 157:493–505CrossRefPubMedGoogle Scholar
  22. Graeff FG, Guimaraes FS, De Andrade TGCS, Deakin JFW (1996) Anxiety and role of 5-HT in stress and anxiety and depression. Pharmacol Biochem Behav 54:129–141CrossRefPubMedGoogle Scholar
  23. Griebel G, Perrault G, Sanger DJ (1997) A comparative study of the effects of selective and non-selective 5-HT2 receptor subtype antagonists in rat and mouse models of anxiety. Neuropharmacology 36:793–802CrossRefPubMedGoogle Scholar
  24. Guardiola-Lemaitre B, Lenegre A, Porsolt RD (1992) Combined effects of diazepam and melatonin in two tests for anxiolytic activity in the mouse. Pharmacol Biochem Behav 41:405CrossRefPubMedGoogle Scholar
  25. Hay-Schmidt A, Vrang N, Larsen PJ, Mikkelsen JD (2003) Projections from the raphe nuclei to the suprachiasmatic nucleus of the rat. J Chem Neurosci 25:293–310CrossRefGoogle Scholar
  26. Jenck F, Bös M, Wichmann J, Stadler H, Martin JR, Moreau JL (1998) The role of 5-HT2C receptors in affective disorders. Exp Opin Invest Drugs 7:1587–1599Google Scholar
  27. Kennaway DJ, Moyer RW (1998) Serotonin 5-HT2C agonists mimic the effect of light pulses on circadian rhythms. Brain Res 806:257–270CrossRefPubMedGoogle Scholar
  28. Kennaway DJ, Moyer RW (1999) MK-801 administration blocks the effects of a 5-HT2A/2C agonist on melatonin rhythmicity and c-fos induction in the suprachiasmatic nucleus. Brain Res 845:102–106CrossRefPubMedGoogle Scholar
  29. Kennaway DJ, Moyer RW, Voultsios A, Varcoe TJ (2001) Serotonin, excitatory amino acids and the photic control of melatonin rhythms and SCN c-fos in the rat. Brain Res 897:36–43CrossRefPubMedGoogle Scholar
  30. Kennett GA, Wood MD, Glen A, Grewal S, Forbes I, Gadre A, Blackburn TP (1994) In vivo properties of SB 200646A, a 5-HT2C/2B receptor antagonist. Br J Pharmacol 111:797–802PubMedGoogle Scholar
  31. Kennett GA, Wood MD, Bright F, Cilia J, Piper DC, Gager T, Thomas D, Baxter GS, Forbes IT, Ham P, Blackburn TP (1996) In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties. Br J Pharmacol 117:427–434PubMedGoogle Scholar
  32. Kennett GA, Wood MD, Bright F, Trail B, Riley G, Holland V, Avenell KY, Stean T, Upton N, Bromidge S, Forbes IT, Brown AM, Middlemiss DN, Blackburn TP (1997) SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36:609–620CrossRefPubMedGoogle Scholar
  33. Kennett GA, Trail B, Bright F (1998) Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated. Neuropharmacology 37:1603–1610CrossRefPubMedGoogle Scholar
  34. Kleven MS, Koek W (1999) Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans. Psychopharmacology 141:206–212Google Scholar
  35. Kopp C, Vogel E, Rettori MC, Delagrange P, Guardiola-Lemaître B, Misslin R (1999a) Effects of melatonin on neophobic responses in different strains in mice. Pharmacol Biochem Behav 63:521–526CrossRefPubMedGoogle Scholar
  36. Kopp C, Vogel E, Rettori MC, Delagrange P, Renard P, Lesieur D, Misslin R (1999b) Antagonistic effects of S22153, a new MT1 and MT2 receptor ligand, on the neophobia-reducing properties of melatonin in BALB/c mice. Pharmacol Biochem Behav 64:131–136CrossRefPubMedGoogle Scholar
  37. Kopp C, Vogel E, Rettori MC, Delagrange P, Misslin R (2000) Anxiolytic-like properties of melatonin receptor agonists in mice: involvement of MT1 and/or MT2 receptors in the regulation of emotional responsiveness. Neuropharmacology 39:1865–1871CrossRefPubMedGoogle Scholar
  38. Krueger KE (1991) Peripheral-type benzodiazepine receptors: a second site of action for benzodiazepines. Neuropharmacology 4:237–244Google Scholar
  39. Liu C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff VK, Reppert SM (1997) Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19:91–102CrossRefPubMedGoogle Scholar
  40. Lôo H, D’haenen H, Hale A (2002a) A double-blind study of S20098 in patients with major depressive or bipolar II disorders: effect on anxiety. Int J Neuropsychopharmacol 5:P3.E.031Google Scholar
  41. Lôo H, Hale A, D’haenen H. (2002b) Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder. A placebo controlled dose range study. Int Clin Psychopharmacol 17:239–247PubMedGoogle Scholar
  42. Lopez-Gimenez J, Tecott LH, Palacios JM (2002) Serotonin 5-HT2C receptor knockout mice: autoradiographic analysis of multiple serotonin receptors. J Neurosci Res 67:69–85CrossRefPubMedGoogle Scholar
  43. Menard J, Treit D (1999) Effects of centrally administered anxiolytic compounds in animal models of anxiety. Neurosci Biobehav Rev 23:591–613CrossRefPubMedGoogle Scholar
  44. Miczek KA, Weerts E, Vivian JA, Barros HM (1995) Aggression, anxiety and vocalizations in animals: GABAA and 5-HT anxiolytics. Psychopharmacology 121:38–56PubMedGoogle Scholar
  45. Millan MJ (2003) The neurobiology and control of anxious states. Prog Neurobiol 70:53–244CrossRefPubMedGoogle Scholar
  46. Millan MJ, Brocco M (2003) The Vogel conflict test: procedural aspects, γ-aminobutyric acid, glutamate and monoamines. Eur J Pharmacol 463:67–96CrossRefPubMedGoogle Scholar
  47. Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, Dekeyne A, Nicolas JP, Lejeune F (2000a) Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of α2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur J Neurosci 12:1079–1095CrossRefPubMedGoogle Scholar
  48. Millan MJ, Lejeune F, Gobert A (2000b) Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents. J Psychopharmacol 14:114–138PubMedGoogle Scholar
  49. Millan MJ, Brocco M, Gobert A, Dorey G, Casara P, Dekeyne A (2001) Anxiolytic properties of the selective, non-peptidergic CRF1 antagonists, CP154,526 and DMP695: a comparison to other classes of anxiolytic agent. Neuropsychopharmacology 25:585–600CrossRefPubMedGoogle Scholar
  50. Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet J-M, 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 306:954–964CrossRefPubMedGoogle Scholar
  51. Molewijk HE, van der Poel AM, Mos J, van der Heyden JAM, Olivier B (1995) Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs. Psychopharmacology 117:32–40PubMedGoogle Scholar
  52. Naguib M, Samarkandi AH (2000) The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg 91:473–479PubMedGoogle Scholar
  53. Naranjo-Rodriguez EB, Ortiz Orsornio A, Hernandez-Avitia E, Mendoza-Fernandez V, Escobar A (2000) Anxiolytic-like actions of melatonin, 5-methoxytryptophan, 5-hydroxytryptophol and benzodiazepines on a conflict procedure. Prog Neuropsychopharmacol Biol Psychiatr 24:117–129CrossRefGoogle Scholar
  54. Nava F, Carta G (2001) Melatonin reduces anxiety induced by lipopolysaccharide in the rat. Neurosci Lett 307:57–60CrossRefPubMedGoogle Scholar
  55. Niles L (1991) Melatonin interaction with the benzodiazepine-GABA receptor complex in the CNS. Adv Exp Med Biol 294:267–277PubMedGoogle Scholar
  56. 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 28:694–703CrossRefPubMedGoogle Scholar
  57. Pierrefiche G, Zerbib R, Laborit H (1993) Anxiolytic activity of melatonin in mice: involvement of benzodiazepine receptors. Res Commun Chem Pathol Pharmacol 82:131–142PubMedGoogle Scholar
  58. Roca AL, Weaver DR, Reppert SM (1993) Serotonin receptor gene expression in the rat suprachiasmatic nuclei. Brain Res 608:159–165CrossRefPubMedGoogle Scholar
  59. Rocha B, Rigo M, Di Scala G, Sandner G, Hoyer D (1994) Chronic mianserin or eltoprazine treatment in rats: effects on the elevated plus-maze test and on limbic 5-HT2C receptor levels. Eur J Pharmacol 262:125–131CrossRefPubMedGoogle Scholar
  60. Sanger DJ (1985) GABA and the behavioural effects of anxiolytic drugs. Life Sci 36:1503–1513CrossRefPubMedGoogle Scholar
  61. Sánchez C (2003) Stress-induced vocalization in adult animals. A valid model of anxiety? Eur J Pharmacol 463:133–143CrossRefPubMedGoogle Scholar
  62. Sànchez C, Mørk A (1999) N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline studies on the role of 5-HT1A and 5-HT2 receptors in mediating foot-shock-induced ultrasonic vocalisation in adults rats. Eur Neuropsychopharmacol 9:287–294CrossRefPubMedGoogle Scholar
  63. Tanaka M, Yoshida M, Emoto H, Ishii H (2000) Noradrenaline systems in the hypothalamus, amydgala and locus coeruleus are involved in the provocation of anxiety: basic studies. Eur J Pharmacol 405:397–406CrossRefPubMedGoogle Scholar
  64. Van Reeth O, Weibel L, Olivares E, Maccari S, Mocaër E, Turek FW (2001) Melatonin or a melatonin agonist correct age-related changes in circadian response to an environmental stimulus. Am J Physiol 280:1582–1591Google Scholar
  65. Wall PM, Messier C (2001) Methodological and conceptual issues in the use of the elevated plus-maze as a psychological measurement instrument of animal anxiety-like behavior. Neurosci Biobehav Rev 25:275–286CrossRefPubMedGoogle Scholar
  66. Weibel L, Retorri MC, Lesieur D, Delagrange P, Renard P, Van Reeth O (1999) A single oral dose of S22153, a melatonin antagonist, blocks the phase advancing effects of melatonin in C3H mice. Brain Res 829:160–166CrossRefPubMedGoogle Scholar
  67. Wiley JL, Dance ME, Balster BL (1998) Preclinical evaluation of the reinforcing and discriminative stimulus effects of agomelatine (S20098), a melatonin agonist. Psychopharmacology 140:503–509Google Scholar
  68. Wood MD, Reavill C, Trail B, Wilson A, Stean T, Kennett GA, Lightowler S, Blackburn TP, Thomas D, Gager TL, Riley G, Holland V, Bromidge SM, Forbes IT, Middlemiss DN (2001) SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. Neuropharmacology 41:186–199CrossRefPubMedGoogle Scholar
  69. Ying SW, Rusak B, Delagrange P (1996) Melatonin analogues as agonist and antagonists in the circadian system and other brain areas. Eur J Pharmacol 296:33–42CrossRefPubMedGoogle Scholar
  70. Yoshioka K, Xie F, Gitzen JF, Kissinger CB, Kissinger PT (2000) Preliminary study of the effects of melatonin administration on the release of endogenous 5-HT and its metabolite in rat SCN. Curr Separation 18:117–122Google Scholar
  71. Yous S, Andrieux J, Howell HE, Morgan PJ, Renard P, Pfeiffer B, Lesieur D, Guardiola-Lemaître B (1992) Novel naphtalenic ligands with high affinity for the melatonin receptor. J Med Chem 35:1484–1585PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Mark J. Millan
    • 1
    Email author
  • Mauricette Brocco
    • 1
  • Alain Gobert
    • 1
  • Anne Dekeyne
    • 1
  1. 1.Department of Psychopharmacology, Centre de Recherches de CroissyInstitut de Recherches ServierParisFrance

Personalised recommendations