Skip to main content
SpringerLink
Log in

Melatonin Induces Antidepressant-Like Behavior by Promotion of Adult Hippocampal Neurogenesis

  • Chapter
  • First Online:
Melatonin, Neuroprotective Agents and Antidepressant Therapy

  • 1620 Accesses

Abstract

Adult hippocampal neurogenesis is a widely regulated process. The generation of new neurons is affected in some neuropsychiatric disorders including depression. In particular, information from preclinical studies has shown that every substance with an antidepressant effect could also regulate adult hippocampal neurogenesis. In this regard, melatonin has gained attention due to its antidepressant-like effects and its capacity to regulate adult hippocampal neurogenesis. Based on that, in this chapter I review the information related to the effects of melatonin as an antidepressant factor that is related to adult hippocampal neurogenesis. I apologize if I failed to cite works related to the content of this chapter; however, I tried to briefly cover the most significant aspects of melatonin, hippocampal neurogenesis, and melatonin’s antidepressant-like effects.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev. 1991;12:151–80.

    Article  CAS  PubMed  Google Scholar 

  2. Tan DX, Reiter RJ, Manchester LC, et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2002;2:181–97.

    Article  CAS  PubMed  Google Scholar 

  3. Kennaway DJ, Voultsios A, Varcoe TJ, et al. Melatonin in mice: rhythms, response to light, adrenergic stimulation, and metabolism. Am J Physiol Regul Integr Comp Physiol. 2002;282:R358–65.

    Article  CAS  PubMed  Google Scholar 

  4. Darcourt G, Souetre E, Pringuey D, et al. Disorders of circadian rhythms in depression. Encéphale. 1992;18(Spec No 4):473–8.

    PubMed  Google Scholar 

  5. Armitage R. Sleep and circadian rhythms in mood disorders. Acta Psychiatr Scand Suppl. 2007;115(433):104–15.

    Google Scholar 

  6. Carvalho LA, Gorenstein C, Moreno R, et al. Effect of antidepressants on melatonin metabolite in depressed patients. J Psychopharmacol. 2009;23:315–21.

    Article  CAS  PubMed  Google Scholar 

  7. Ballmaier M, Narr KL, Toga AW, et al. Hippocampal morphology and distinguishing late-onset from early-onset elderly depression. Am J Psychiatry. 2008;165:229–37.

    Article  PubMed  Google Scholar 

  8. Thase ME. Depression, sleep, and antidepressants. J Clin Psychiatry. 1998;59 Suppl 4:55–65.

    CAS  PubMed  Google Scholar 

  9. O’Connor TM, O’Halloran DJ, Shanahan F. The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia. QJM. 2000;93:323–33.

    Article  PubMed  Google Scholar 

  10. Jayatissa MN, Bisgaard CF, West MJ, et al. The number of granule cells in rat hippocampus is reduced after chronic mild stress and re-established after chronic escitalopram treatment. Neuropharmacology. 2008;54:530–41.

    Article  CAS  PubMed  Google Scholar 

  11. Garcia A, Steiner B, Kronenberg G, et al. Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus. Aging Cell. 2004;3:363–71.

    Article  CAS  PubMed  Google Scholar 

  12. Jaako-Movits K, Zharkovsky T, Pedersen M, et al. Decreased hippocampal neurogenesis following olfactory bulbectomy is reversed by repeated citalopram administration. Cell Mol Neurobiol. 2006;26:1559–70.

    Article  CAS  PubMed  Google Scholar 

  13. Sahay A, Hen R. Hippocampal neurogenesis and depression. Novartis Found Symp. 2008;289:152–60. discussion 160–4, 193–5.

    Article  CAS  PubMed  Google Scholar 

  14. Kempermann G, Krebs J, Fabel K. The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Curr Opin Psychiatr. 2008;21:290–5.

    Article  Google Scholar 

  15. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–5.

    Article  CAS  PubMed  Google Scholar 

  16. Kempermann G, Jessberger S, Steiner B, et al. Milestones of neuronal development in the adult hippocampus. Trends Neurosci. 2004;27:447–52.

    Article  CAS  PubMed  Google Scholar 

  17. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132:645–60.

    Article  CAS  PubMed  Google Scholar 

  18. Brandt MD, Jessberger S, Steiner B, et al. Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice. Mol Cell Neurosci. 2003;24:603–13.

    Article  CAS  PubMed  Google Scholar 

  19. Knoth R, Singec I, Ditter M, et al. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS One. 2010;5:e8809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Plumpe T, Ehninger D, Steiner B, et al. Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation. BMC Neurosci. 2006;7:77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Song H, Kempermann G, Overstreet Wadiche L, et al. New neurons in the adult mammalian brain: synaptogenesis and functional integration. J Neurosci. 2005;25:10366–8.

    Article  CAS  PubMed  Google Scholar 

  22. Boldrini M, Arango V. Antidepressants, age, and neuroprogenitors. Neuropsychopharmacology. 2010;35:351–2.

    Article  PubMed  Google Scholar 

  23. van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci. 2000;1:191–8.

    Article  CAS  PubMed  Google Scholar 

  24. Winner B, Kohl Z, Gage FH. Neurodegenerative disease and adult neurogenesis. Eur J Neurosci. 2011;33:1139–51.

    Article  PubMed  Google Scholar 

  25. Hattiangady B, Shetty AK. Implications of decreased hippocampal neurogenesis in chronic temporal lobe epilepsy. Epilepsia. 2008;49 Suppl 5:26–41.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tanti A, Belzung C. Hippocampal neurogenesis: a biomarker for depression or antidepressant effects? Methodological considerations and perspectives for future research. Cell Tissue Res. 2013;354:203–19.

    Article  CAS  PubMed  Google Scholar 

  27. Tanti A, Belzung C. Neurogenesis along the septo-temporal axis of the hippocampus: are depression and the action of antidepressants region-specific? Neuroscience. 2013;252:234–52.

    Article  CAS  PubMed  Google Scholar 

  28. Klempin F, Babu H, DE Pietri Tonelli D, et al. Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci. 2010;3:14.

    PubMed  PubMed Central  Google Scholar 

  29. Taliaz D, Stall N, Dar DE, et al. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry. 2010;15:80–92.

    Article  CAS  PubMed  Google Scholar 

  30. Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A. 2008;105:751–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Boldrini M, Underwood MD, Hen R, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009;34:2376–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jacobs BL. Adult brain neurogenesis and depression. Brain Behav Immun. 2002;16:602–9.

    Article  CAS  PubMed  Google Scholar 

  33. Crasson M, Kjiri S, Colin A, et al. Serum melatonin and urinary 6-sulfatoxymelatonin in major depression. Psychoneuroendocrinology. 2004;29:1–12.

    Article  CAS  PubMed  Google Scholar 

  34. Detanico BC, Piato AL, Freitas JJ, et al. Antidepressant-like effects of melatonin in the mouse chronic mild stress model. Eur J Pharmacol. 2009;607:121–5.

    Article  CAS  PubMed  Google Scholar 

  35. Haridas S, Kumar M, Manda K. Melatonin ameliorates chronic mild stress induced behavioral dysfunctions in mice. Physiol Behav. 2013;119:201–7.

    Article  CAS  PubMed  Google Scholar 

  36. Kopp C, Vogel E, Rettori MC, et al. The effects of melatonin on the behavioural disturbances induced by chronic mild stress in C3H/He mice. Behav Pharmacol. 1999;10:73–83.

    Article  CAS  PubMed  Google Scholar 

  37. Raghavendra V, Kaur G, Kulkarni SK. Anti-depressant action of melatonin in chronic forced swimming-induced behavioral despair in mice, role of peripheral benzodiazepine receptor modulation. Eur Neuropsychopharmacol. 2000;10:473–81.

    Article  CAS  PubMed  Google Scholar 

  38. Hill MN, Brotto LA, Lee TT, et al. Corticosterone attenuates the antidepressant-like effects elicited by melatonin in the forced swim test in both male and female rats. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:905–11.

    Article  CAS  PubMed  Google Scholar 

  39. Micale V, Arezzi A, Rampello L, et al. Melatonin affects the immobility time of rats in the forced swim test: the role of serotonin neurotransmission. Eur Neuropsychopharmacol. 2006;16:538–45.

    Article  CAS  PubMed  Google Scholar 

  40. Binfare RW, Mantovani M, Budni J, et al. Involvement of dopamine receptors in the antidepressant-like effect of melatonin in the tail suspension test. Eur J Pharmacol. 2010;638:78–83.

    Article  CAS  PubMed  Google Scholar 

  41. Nagy AD, Iwamoto A, Kawai M, et al. Melatonin adjusts the expression pattern of clock genes in the suprachiasmatic nucleus and induces antidepressant-like effect in a mouse model of seasonal affective disorder. Chronobiol Int. 2015;32:447–57.

    Article  CAS  PubMed  Google Scholar 

  42. Bassani TB, Gradowski RW, Zaminelli T, et al. Neuroprotective and antidepressant-like effects of melatonin in a rotenone-induced Parkinson’s disease model in rats. Brain Res. 2014;1593:95–105.

    Article  CAS  PubMed  Google Scholar 

  43. Henn FA, Vollmayr B. Neurogenesis and depression: etiology or epiphenomenon? Biol Psychiatry. 2004;56:146–50.

    Article  PubMed  Google Scholar 

  44. Ramirez-Rodriguez G, Klempin F, Babu H, et al. Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychopharmacology. 2009;34:2180–91.

    Article  CAS  PubMed  Google Scholar 

  45. Ramirez-Rodriguez G, Ortiz-Lopez L, Dominguez-Alonso A, et al. Chronic treatment with melatonin stimulates dendrite maturation and complexity in adult hippocampal neurogenesis of mice. J Pineal Res. 2011;50:29–37.

    Article  CAS  PubMed  Google Scholar 

  46. Ramirez-Rodriguez G, Vega-Rivera NM, Benitez-King G, et al. Melatonin supplementation delays the decline of adult hippocampal neurogenesis during normal aging of mice. Neurosci Lett. 2012;530:53–8.

    Article  CAS  PubMed  Google Scholar 

  47. Liu J, Somera-Molina KC, Hudson RL, et al. Melatonin potentiates running wheel-induced neurogenesis in the dentate gyrus of adult C3H/HeN mice hippocampus. J Pineal Res. 2013;54:222–31.

    Article  CAS  PubMed  Google Scholar 

  48. Kempermann G, Kuhn HG, Gage FH. Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc Natl Acad Sci U S A. 1997;94:10409–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kim MJ, Kim HK, Kim BS, et al. Melatonin increases cell proliferation in the dentate gyrus of maternally separated rats. J Pineal Res. 2004;37:193–7.

    Article  CAS  PubMed  Google Scholar 

  50. Crupi R, Mazzon E, Marino A, et al. Melatonin treatment mimics the antidepressant action in chronic corticosterone-treated mice. J Pineal Res. 2010;49:123–9.

    CAS  PubMed  Google Scholar 

  51. Crupi R, Mazzon E, Marino A, et al. Melatonin’s stimulatory effect on adult hippocampal neurogenesis in mice persists after ovariectomy. J Pineal Res. 2011;51:353–60.

    Article  CAS  PubMed  Google Scholar 

  52. Banasr M, Soumier A, Hery M, et al. Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biol Psychiatry. 2006;59:1087–96.

    Article  CAS  PubMed  Google Scholar 

  53. Bourin M, Prica C. Melatonin receptor agonist agomelatine: a new drug for treating unipolar depression. Curr Pharm Des. 2009;15:1675–82.

    Article  CAS  PubMed  Google Scholar 

  54. Eser D, Baghai TC, Moller HJ. Evidence of agomelatine’s antidepressant efficacy: the key points. Int Clin Psychopharmacol. 2007;22 Suppl 2:S15–9.

    Article  PubMed  Google Scholar 

  55. Alahmed S, Herbert J. Effect of agomelatine and its interaction with the daily corticosterone rhythm on progenitor cell proliferation in the dentate gyrus of the adult rat. Neuropharmacology. 2010;59:375–9.

    Article  CAS  PubMed  Google Scholar 

  56. Morley-Fletcher S, Mairesse J, Soumier A, et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacol (Berl). 2011;217:301–13.

    Article  CAS  Google Scholar 

  57. Racagni G, Riva MA, Molteni R, et al. Mode of action of agomelatine: synergy between melatonergic and 5-HT2C receptors. World J Biol Psychiatry. 2011;12:574–87.

    Article  PubMed  Google Scholar 

  58. Soumier A, Banasr M, Lortet S, et al. Mechanisms contributing to the phase-dependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus. Neuropsychopharmacology. 2009;34:2390–403.

    Article  CAS  PubMed  Google Scholar 

  59. Fava M, Rush AJ. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psychosom. 2006;75:139–53.

    Article  PubMed  Google Scholar 

  60. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    Article  PubMed  Google Scholar 

  61. Thase ME, Howland RH, Friedman ES. Treating antidepressant nonresponders with augmentation strategies: an overview. J Clin Psychiatry. 1998;59 Suppl 5:5–12. discussion 13-5.

    PubMed  Google Scholar 

  62. Ergun Y, Orhan FO, Karaaslan MF. Combination therapy of imipramine and melatonin: additive antidepressant effect in mouse forced swimming test. Eur J Pharmacol. 2008;591:159–63.

    Article  CAS  PubMed  Google Scholar 

  63. Fava M, Targum SD, Nierenberg AA, et al. An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. J Psychiatr Res. 2013;46:1553–63.

    Article  Google Scholar 

  64. Ramirez-Rodriguez G, Vega-Rivera NM, Oikawa-Sala J, et al. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice. J Pineal Res. 2014;56:450–61.

    Article  CAS  PubMed  Google Scholar 

  65. Ekthuwapranee K, Sotthibundhu A, Govitrapong P. Melatonin attenuates methamphetamine-induced inhibition of proliferation of adult rat hippocampal progenitor cells in vitro. J Pineal Res. 2015;58:418–28.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

I would like to thank Chem. Leonardo Ortiz-López for his support in providing images to illustrate the adult hippocampal neurogenic process.

Author information

Authors and Affiliations

  1. Laboratory of Neurogenesis, Division of Clinical Investigations, National Institute of Psychiatry “Ramón de la Fuente Muñiz”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Delegación Tlalpan, C.P. 14370, México, DF, México

    Gerardo Bernabé Ramírez-Rodríguez PhD

Authors
  1. Gerardo Bernabé Ramírez-Rodríguez PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerardo Bernabé Ramírez-Rodríguez PhD .

Editor information

Editors and Affiliations

  1. Vice-Rectorate for Research and Sci, Camilo José Cela University Vice-Rectorate for Research and Sci, Madrid, Spain

    Francisco López-Muñoz

  2. International Medical Sciences Research Study Center, Sri Sathya Sai Medical Educational & Research Foundation, Coimbatore, India

    Venkataramanujam Srinivasan

  3. Department of Neurosciences and Ima, University of Chieti Department of Neurosciences and Ima, Italy, Italy

    Domenico de Berardis

  4. Department of Biomedical Sciences (Pharmacology Area), University of Alcalá, Madrid, Spain

    Cecilio Álamo

  5. Department of Neuropsychiatry, Kyushu University, Fukuoka, Japan

    Takahiro A. Kato

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer India

About this chapter

Cite this chapter

Ramírez-Rodríguez, G.B. (2016). Melatonin Induces Antidepressant-Like Behavior by Promotion of Adult Hippocampal Neurogenesis. In: López-Muñoz, F., Srinivasan, V., de Berardis, D., Álamo, C., Kato, T. (eds) Melatonin, Neuroprotective Agents and Antidepressant Therapy. Springer, New Delhi. https://doi.org/10.1007/978-81-322-2803-5_10

Download citation

  • DOI: https://doi.org/10.1007/978-81-322-2803-5_10

  • Published:

  • Publisher Name: Springer, New Delhi

  • Print ISBN: 978-81-322-2801-1

  • Online ISBN: 978-81-322-2803-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation