Skip to main content

Advertisement

Springer Nature Link
Log in

Melatonin receptors: distribution in mammalian brain and their respective putative functions

  • Review
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

Melatonin, through its different receptors, has pleiotropic functions in mammalian brain. Melatonin is secreted mainly by the pineal gland and exerts its effects via receptor-mediated and non-receptor-mediated actions. With recent advancement in neuroanatomical mapping, we may now understand better the localizations of the two G protein-coupled melatonin receptors MT1 and MT2. The abundance of these melatonin receptors in respective brain regions suggests that receptor-mediated actions of melatonin might play crucial roles in the functions of central nervous system. Hence, this review aims to summarize the distribution of melatonin receptors in the brain and to discuss the putative functions of melatonin in the retina, cerebral cortex, reticular thalamic nucleus, habenula, hypothalamus, pituitary gland, periaqueductal gray, dorsal raphe nucleus, midbrain and cerebellum. Studies on melatonin receptors in the brain are important because cumulative evidence has pointed out that melatonin receptors not only play important physiological roles in sleep, anxiety, pain and circadian rhythm, but might also be involved in the pathogenesis of a number of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

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 includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Adamah-Biassi EB, Zhang Y, Jung H, Vissapragada S, Miller RJ, Dubocovich M (2014) Distribution of MT1 melatonin receptor promoter-driven RFP expression in the brains of BAC C3H/HeN transgenic mice. J Histochem Cytochem Off J Histochem Soc 62(1):70–84. doi:10.1369/0022155413507453

    Article  CAS  Google Scholar 

  • Adi N, Mash DC, Ali Y, Singer C, Shehadeh L, Papapetropoulos S (2010) Melatonin MT1 and MT2 receptor expression in Parkinson’s disease. Med Sci Monit 16(2):Br61–Br67

    CAS  PubMed  Google Scholar 

  • Al-Ghoul WM, Herman MD, Dubocovich ML (1998) Melatonin receptor subtype expression in human cerebellum. NeuroReport 9(18):4063–4068

    Article  CAS  PubMed  Google Scholar 

  • Ambriz-Tututi M, Rocha-Gonzalez HI, Cruz SL, Granados-Soto V (2009) Melatonin: a hormone that modulates pain. Life Sci 84(15–16):489–498. doi:10.1016/j.lfs.2009.01.024

    Article  CAS  PubMed  Google Scholar 

  • Barlow-Walden LR, Reiter RJ, Abe M, Pablos M, Menendez-Pelaez A, Chen LD, Poeggeler B (1995) Melatonin stimulates brain glutathione peroxidase activity. Neurochem Int 26(5):497–502

    Article  CAS  PubMed  Google Scholar 

  • Becker-Andre M, Wiesenberg I, Schaeren-Wiemers N, Andre E, Missbach M, Saurat JH, Carlberg C (1994) Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem 269(46):28531–28534

    CAS  PubMed  Google Scholar 

  • Bordet R, Devos D, Brique S, Touitou Y, Guieu JD, Libersa C, Destee A (2003) Study of circadian melatonin secretion pattern at different stages of Parkinson’s disease. Clin Neuropharmacol 26(2):65–72

    Article  CAS  PubMed  Google Scholar 

  • Boulos LJ, Darcq E, Kieffer BL (2016) Translating the habenula—from rodents to humans. Biol Psychiatry. doi:10.1016/j.biopsych.2016.06.003

    PubMed  Google Scholar 

  • Breen DP, Vuono R, Nawarathna U, Fisher K, Shneerson JM, Reddy AB, Barker RA (2014) Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol 71(5):589–595. doi:10.1001/jamaneurol.2014.65

    Article  PubMed  PubMed Central  Google Scholar 

  • Breen DP, Nombela C, Vuono R, Jones PS, Fisher K, Burn DJ, Brooks DJ, Reddy AB, Rowe JB, Barker RA (2016) Hypothalamic volume loss is associated with reduced melatonin output in Parkinson’s disease. Mov Disord Off J Mov Disord Soc. doi:10.1002/mds.26592

    Google Scholar 

  • Brunner P, Sozer-Topcular N, Jockers R, Ravid R, Angeloni D, Fraschini F, Eckert A, Muller-Spahn F, Savaskan E (2006) Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer’s disease. Eur J Histochem EJH 50(4):311–316

    CAS  PubMed  Google Scholar 

  • Bubenik GA (2002) Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 47(10):2336–2348

    Article  CAS  PubMed  Google Scholar 

  • Buckner RL (2013) The cerebellum and cognitive function: 25 years of insight from anatomy and neuroimaging. Neuron 80(3):807–815. doi:10.1016/j.neuron.2013.10.044

    Article  CAS  PubMed  Google Scholar 

  • Carlson LL, Weaver DR, Reppert SM (1989) Melatonin signal transduction in hamster brain: inhibition of adenylyl cyclase by a pertussis toxin-sensitive G protein. Endocrinology 125(5):2670–2676. doi:10.1210/endo-125-5-2670

    Article  CAS  PubMed  Google Scholar 

  • Cazevieille C, Safa R, Osborne NN (1997) Melatonin protects primary cultures of rat cortical neurones from NMDA excitotoxicity and hypoxia/reoxygenation. Brain Res 768(1–2):120–124

    Article  CAS  PubMed  Google Scholar 

  • Comai S, Gobbi G (2014) CCNP award paper: unveiling the role of melatonin MT(2) receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology. J Psychiatry Neurosci 39(1):6–21. doi:10.1503/jpn.130009

    Article  PubMed  PubMed Central  Google Scholar 

  • Comai S, Ochoa-Sanchez R, Gobbi G (2013) Sleep-wake characterization of double MT(1)/MT(2) receptor knockout mice and comparison with MT(1) and MT(2) receptor knockout mice. Behav Brain Res 243:231–238. doi:10.1016/j.bbr.2013.01.008

    Article  CAS  PubMed  Google Scholar 

  • Comai S, Ochoa-Sanchez R, Dominguez-Lopez S, Bambico FR, Gobbi G (2015) Melancholic-like behaviors and circadian neurobiological abnormalities in melatonin MT1 receptor knockout mice. Int J Neuropsychopharmacol. doi:10.1093/ijnp/pyu075

    PubMed  PubMed Central  Google Scholar 

  • Cooke SF, Bliss TV (2006) Plasticity in the human central nervous system. Brain 129(Pt 7):1659–1673. doi:10.1093/brain/awl082

    Article  CAS  PubMed  Google Scholar 

  • Costa EJ, Lopes RH, Lamy-Freund MT (1995) Permeability of pure lipid bilayers to melatonin. J Pineal Res 19(3):123–126

    Article  CAS  PubMed  Google Scholar 

  • Dardente H, Klosen P, Pevet P, Masson-Pevet M (2003) MT1 melatonin receptor mRNA expressing cells in the pars tuberalis of the European hamster: effect of photoperiod. J Neuroendocrinol 15(8):778–786

    Article  CAS  PubMed  Google Scholar 

  • Deupi X, Dolker N, Lopez-Rodriguez ML, Campillo M, Ballesteros JA, Pardo L (2007) Structural models of class a G protein-coupled receptors as a tool for drug design: insights on transmembrane bundle plasticity. Curr Top Med Chem 7(10):991–998

    Article  CAS  PubMed  Google Scholar 

  • Dominguez-Lopez S, Mahar I, Bambico FR, Labonte B, Ochoa-Sanchez R, Leyton M, Gobbi G (2012) Short-term effects of melatonin and pinealectomy on serotonergic neuronal activity across the light–dark cycle. J Psychopharmacol 26(6):830–844. doi:10.1177/0269881111408460

    Article  PubMed  CAS  Google Scholar 

  • Dubocovich ML, Markowska M (2005) Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 27(2):101–110. doi:10.1385/endo:27:2:101

    Article  CAS  PubMed  Google Scholar 

  • Dubocovich ML, Benloucif S, Masana MI (1996) Melatonin receptors in the mammalian suprachiasmatic nucleus. Behav Brain Res 73(1–2):141–147

    CAS  PubMed  Google Scholar 

  • Dubocovich ML, Hudson RL, Sumaya IC, Masana MI, Manna E (2005) Effect of MT1 melatonin receptor deletion on melatonin-mediated phase shift of circadian rhythms in the C57BL/6 mouse. J Pineal Res 39(2):113–120. doi:10.1111/j.1600-079X.2005.00230.x

    Article  CAS  PubMed  Google Scholar 

  • Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J (2010) International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev 62(3):343–380. doi:10.1124/pr.110.002832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ebisawa T, Karne S, Lerner MR, Reppert SM (1994) Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores. Proc Natl Acad Sci USA 91(13):6133–6137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ekthuwapranee K, Sotthibundhu A, Govitrapong P (2015) Melatonin attenuates methamphetamine-induced inhibition of proliferation of adult rat hippocampal progenitor cells in vitro. J Pineal Res 58(4):418–428. doi:10.1111/jpi.12225

    Article  CAS  PubMed  Google Scholar 

  • El-Sherif Y, Witt-Enderby P, Li PK, Tesoriero J, Hogan MV, Wieraszko A (2004) The actions of a charged melatonin receptor ligand, TMEPI, and an irreversible MT2 receptor agonist, BMNEP, on mouse hippocampal evoked potentials in vitro. Life Sci 75(26):3147–3156. doi:10.1016/j.lfs.2004.06.009

    Article  CAS  PubMed  Google Scholar 

  • Esparza JL, Gomez M, Rosa Nogues M, Paternain JL, Mallol J, Domingo JL (2005) Melatonin reduces oxidative stress and increases gene expression in the cerebral cortex and cerebellum of aluminum-exposed rats. J Pineal Res 39(2):129–136. doi:10.1111/j.1600-079X.2005.00225.x

    Article  CAS  PubMed  Google Scholar 

  • Evely KM, Hudson RL, Dubocovich ML, Haj-Dahmane S (2016) Melatonin receptor activation increases glutamatergic synaptic transmission in the rat medial lateral habenula. Synapse (New York, NY) 70(5):181–186. doi:10.1002/syn.21892

    Article  CAS  Google Scholar 

  • Fisher SP, Sugden D (2009) Sleep-promoting action of IIK7, a selective MT2 melatonin receptor agonist in the rat. Neurosci Lett 457(2):93–96. doi:10.1016/j.neulet.2009.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fraschini F, Cesarani A, Alpini D, Esposti D, Stankov BM (1999) Melatonin influences human balance. Biol Signals Recept 8(1–2):111–119. doi:10.1159/000014578

    Article  CAS  PubMed  Google Scholar 

  • Fujieda H, Hamadanizadeh SA, Wankiewicz E, Pang SF, Brown GM (1999) Expression of mt1 melatonin receptor in rat retina: evidence for multiple cell targets for melatonin. Neuroscience 93(2):793–799

    Article  CAS  PubMed  Google Scholar 

  • Fujieda H, Scher J, Hamadanizadeh SA, Wankiewicz E, Pang SF, Brown GM (2000) Dopaminergic and GABAergic amacrine cells are direct targets of melatonin: immunocytochemical study of mt1 melatonin receptor in guinea pig retina. Vis Neurosci 17(1):63–70

    Article  CAS  PubMed  Google Scholar 

  • Galano A, Tan DX, Reiter RJ (2013) On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. J Pineal Res 54(3):245–257. doi:10.1111/jpi.12010

    Article  CAS  PubMed  Google Scholar 

  • Gilgun-Sherki Y, Melamed E, Offen D (2001) Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40(8):959–975

    Article  CAS  PubMed  Google Scholar 

  • Graeff FG (2012) New perspective on the pathophysiology of panic: merging serotonin and opioids in the periaqueductal gray. Braz J Med Biol Res Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica [et al] 45(4):366–375

    CAS  Google Scholar 

  • Hardeland R (2009) Melatonin: signaling mechanisms of a pleiotropic agent. BioFactors 35(2):183–192. doi:10.1002/biof.23

    Article  CAS  PubMed  Google Scholar 

  • Harsanyi K, Mangel SC (1992) Activation of a D2 receptor increases electrical coupling between retinal horizontal cells by inhibiting dopamine release. Proc Natl Acad Sci USA 89(19):9220–9224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herbert J (1994) The suprachiasmatic nucleus. The mind’s clock. J Anat 184(Pt 2):431

    PubMed Central  Google Scholar 

  • Hunt AE, Al-Ghoul WM, Gillette MU, Dubocovich ML (2001) Activation of MT(2) melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am J Physiol Cell Physiol 280(1):C110–C118

    CAS  PubMed  Google Scholar 

  • Jilg A, Moek J, Weaver DR, Korf HW, Stehle JH, von Gall C (2005) Rhythms in clock proteins in the mouse pars tuberalis depend on MT1 melatonin receptor signalling. Eur J Neurosci 22(11):2845–2854. doi:10.1111/j.1460-9568.2005.04485.x

    Article  PubMed  Google Scholar 

  • Jin X, von Gall C, Pieschl RL, Gribkoff VK, Stehle JH, Reppert SM, Weaver DR (2003) Targeted disruption of the mouse Mel(1b) melatonin receptor. Mol Cell Biol 23(3):1054–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jockers R, Maurice P, Boutin JA, Delagrange P (2008) Melatonin receptors, heterodimerization, signal transduction and binding sites: what’s new? Br J Pharmacol 154(6):1182–1195. doi:10.1038/bjp.2008.184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klosen P, Bienvenu C, Demarteau O, Dardente H, Guerrero H, Pevet P, Masson-Pevet M (2002) The mt1 melatonin receptor and RORbeta receptor are co-localized in specific TSH-immunoreactive cells in the pars tuberalis of the rat pituitary. J Histochem Cytochem Off J Histochem Soc 50(12):1647–1657

    Article  CAS  Google Scholar 

  • Kotler M, Rodriguez C, Sainz RM, Antolin I, Menendez-Pelaez A (1998) Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res 24(2):83–89

    Article  CAS  PubMed  Google Scholar 

  • Lacoste B, Angeloni D, Dominguez-Lopez S, Calderoni S, Mauro A, Fraschini F, Descarries L, Gobbi G (2015) Anatomical and cellular localization of melatonin MT1 and MT2 receptors in the adult rat brain. J Pineal Res 58(4):397–417. doi:10.1111/jpi.12224

    Article  CAS  PubMed  Google Scholar 

  • Lahiri DK, Chen D, Ge YW, Bondy SC, Sharman EH (2004) Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. J Pineal Res 36(4):224–231. doi:10.1111/j.1600-079X.2004.00121.x

    Article  CAS  PubMed  Google Scholar 

  • Lakin ML, Miller CH, Stott ML, Winters WD (1981) Involvement of the pineal gland and melatonin in murine analgesia. Life Sci 29(24):2543–2551

    Article  CAS  PubMed  Google Scholar 

  • Larson J, Jessen RE, Uz T, Arslan AD, Kurtuncu M, Imbesi M, Manev H (2006) Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice. Neurosci Lett 393(1):23–26. doi:10.1016/j.neulet.2005.09.040

    Article  CAS  PubMed  Google Scholar 

  • Lee CH, Yoo KY, Choi JH, Park OK, Hwang IK, Kwon YG, Kim YM, Won MH (2010) Melatonin’s protective action against ischemic neuronal damage is associated with up-regulation of the MT2 melatonin receptor. J Neurosci Res 88(12):2630–2640. doi:10.1002/jnr.22430

    CAS  PubMed  Google Scholar 

  • 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(1):91–102

    Article  CAS  PubMed  Google Scholar 

  • Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF (1999) Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab 84(1):323–327. doi:10.1210/jcem.84.1.5394

    CAS  PubMed  Google Scholar 

  • Liu YJ, Zhuang J, Zhu HY, Shen YX, Tan ZL, Zhou JN (2007) Cultured rat cortical astrocytes synthesize melatonin: absence of a diurnal rhythm. J Pineal Res 43(3):232–238. doi:10.1111/j.1600-079X.2007.00466.x

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Somera-Molina KC, Hudson RL, Dubocovich ML (2013) Melatonin potentiates running wheel-induced neurogenesis in the dentate gyrus of adult C3H/HeN mice hippocampus. J Pineal Res 54(2):222–231. doi:10.1111/jpi.12023

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Canul M, Comai S, Dominguez-Lopez S, Granados-Soto V, Gobbi G (2015a) Antinociceptive properties of selective MT(2) melatonin receptor partial agonists. Eur J Pharmacol 764:424–432. doi:10.1016/j.ejphar.2015.07.010

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Canul M, Palazzo E, Dominguez-Lopez S, Luongo L, Lacoste B, Comai S, Angeloni D, Fraschini F, Boccella S, Spadoni G, Bedini A, Tarzia G, Maione S, Granados-Soto V, Gobbi G (2015b) Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways. Pain 156(2):305–317. doi:10.1097/01.j.pain.0000460311.71572.5f

    Article  CAS  PubMed  Google Scholar 

  • Lowenstein PR, Rosenstein R, Cardinali DP (1985) Melatonin reverses pinealectomy-induced decrease of benzodiazepine binding in rat cerebral cortex. Neurochem Int 7(4):675–681

    Article  CAS  PubMed  Google Scholar 

  • Luchetti F, Canonico B, Betti M, Arcangeletti M, Pilolli F, Piroddi M, Canesi L, Papa S, Galli F (2010) Melatonin signaling and cell protection function. Faseb J 24(10):3603–3624. doi:10.1096/fj.10-154450

    Article  CAS  PubMed  Google Scholar 

  • Manda K, Ueno M, Anzai K (2008) Melatonin mitigates oxidative damage and apoptosis in mouse cerebellum induced by high-LET 56Fe particle irradiation. J Pineal Res 44(2):189–196. doi:10.1111/j.1600-079X.2007.00507.x

    Article  CAS  PubMed  Google Scholar 

  • Manto M, Bower JM, Conforto AB, Delgado-García Jé M, da Guarda SNF, Gerwig M, Habas C, Hagura N, Ivry RB, Mariën P, Molinari M, Naito E, Nowak DA, Ben Taib NO, Pelisson D, Tesche CD, Tilikete C, Timmann D (2012) Consensus paper: roles of the cerebellum in motor control—the diversity of ideas on cerebellar involvement in movement. Cerebellum 11(2):457–487. doi:10.1007/s12311-011-0331-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Marangos PJ, Patel J, Hirata F, Sondhein D, Paul SM, Skolnick P, Goodwin FK (1981) Inhibition of diazepam binding by tryptophan derivatives including melatonin and its brain metabolite N-acetyl-5-methoxy kynurenamine. Life Sci 29(3):259–267

    Article  CAS  PubMed  Google Scholar 

  • Masson-Pevet M, George D, Kalsbeek A, Saboureau M, Lakhdar-Ghazal N, Pevet P (1994) An attempt to correlate brain areas containing melatonin-binding sites with rhythmic functions: a study in five hibernator species. Cell Tissue Res 278(1):97–106

    Article  CAS  PubMed  Google Scholar 

  • Matzuk MM, Saper CB (1985) Preservation of hypothalamic dopaminergic neurons in Parkinson’s disease. Ann Neurol 18(5):552–555. doi:10.1002/ana.410180507

    Article  CAS  PubMed  Google Scholar 

  • Mazzucchelli C, Pannacci M, Nonno R, Lucini V, Fraschini F, Stankov BM (1996) The melatonin receptor in the human brain: cloning experiments and distribution studies. Brain Res Mol Brain Res 39(1–2):117–126

    Article  CAS  PubMed  Google Scholar 

  • Megaw PL, Boelen MG, Morgan IG, Boelen MK (2006) Diurnal patterns of dopamine release in chicken retina. Neurochem Int 48(1):17–23. doi:10.1016/j.neuint.2005.08.004

    Article  CAS  PubMed  Google Scholar 

  • Meyer P, Pache M, Loeffler KU, Brydon L, Jockers R, Flammer J, Wirz-Justice A, Savaskan E (2002) Melatonin MT-1-receptor immunoreactivity in the human eye. Br J Ophthalmol 86(9):1053–1057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan PJ, Barrett P, Howell HE, Helliwell R (1994) Melatonin receptors: localization, molecular pharmacology and physiological significance. Neurochem Int 24(2):101–146

    Article  CAS  PubMed  Google Scholar 

  • Musshoff U, Riewenherm D, Berger E, Fauteck JD, Speckmann EJ (2002) Melatonin receptors in rat hippocampus: molecular and functional investigations. Hippocampus 12(2):165–173. doi:10.1002/hipo.1105

    Article  CAS  PubMed  Google Scholar 

  • Neu JM, Niles LP (1997) A marked diurnal rhythm of melatonin ML1A receptor mRNA expression in the suprachiasmatic nucleus. Brain Res Mol Brain Res 49(1–2):303–306

    Article  CAS  PubMed  Google Scholar 

  • Nosjean O, Ferro M, Coge F, Beauverger P, Henlin JM, Lefoulon F, Fauchere JL, Delagrange P, Canet E, Boutin JA (2000) Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 275(40):31311–31317. doi:10.1074/jbc.M005141200

    Article  CAS  PubMed  Google Scholar 

  • Ochoa-Sanchez R, Comai S, Lacoste B, Bambico FR, Dominguez-Lopez S, Spadoni G, Rivara S, Bedini A, Angeloni D, Fraschini F, Mor M, Tarzia G, Descarries L, Gobbi G (2011) Promotion of non-rapid eye movement sleep and activation of reticular thalamic neurons by a novel MT2 melatonin receptor ligand. J Neurosci 31(50):18439–18452. doi:10.1523/jneurosci.2676-11.2011

    Article  CAS  PubMed  Google Scholar 

  • Ochoa-Sanchez R, Comai S, Spadoni G, Bedini A, Tarzia G, Gobbi G (2014) Melatonin, selective and non-selective MT1/MT2 receptors agonists: differential effects on the 24-h vigilance states. Neurosci Lett 561:156–161. doi:10.1016/j.neulet.2013.12.069

    Article  CAS  PubMed  Google Scholar 

  • O’Neal-Moffitt G, Pilli J, Kumar SS, Olcese J (2014) Genetic deletion of MT(1)/MT(2) melatonin receptors enhances murine cognitive and motor performance. Neuroscience 277:506–521. doi:10.1016/j.neuroscience.2014.07.018

    Article  PubMed  CAS  Google Scholar 

  • O’Neal-Moffitt G, Delic V, Bradshaw PC, Olcese J (2015) Prophylactic melatonin significantly reduces Alzheimer’s neuropathology and associated cognitive deficits independent of antioxidant pathways in AbetaPP(swe)/PS1 mice. Mol Neurodegener 10:27. doi:10.1186/s13024-015-0027-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Parada E, Buendia I, Leon R, Negredo P, Romero A, Cuadrado A, Lopez MG, Egea J (2014) Neuroprotective effect of melatonin against ischemia is partially mediated by alpha-7 nicotinic receptor modulation and HO-1 overexpression. J Pineal Res 56(2):204–212. doi:10.1111/jpi.12113

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2013) The rat brain in stereotaxic coordinates, 7th edn. Elsevier Academic Press, San Diego

    Google Scholar 

  • Pechanova O, Paulis L, Simko F (2014) Peripheral and central effects of melatonin on blood pressure regulation. Int J Mol Sci 15(10):17920–17937. doi:10.3390/ijms151017920

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Petit L, Lacroix I, de Coppet P, Strosberg AD, Jockers R (1999) Differential signaling of human Mel1a and Mel1b melatonin receptors through the cyclic guanosine 3′–5′-monophosphate pathway. Biochem Pharmacol 58(4):633–639

    Article  CAS  PubMed  Google Scholar 

  • Pévet P (2002) Melatonin. Dialogues Clin Neurosci 4(1):57–72

    PubMed  PubMed Central  Google Scholar 

  • Pinato L, da Silveira Cruz-Machado S, Franco DG, Campos LMG, Cecon E, Fernandes P, Bittencourt JC, Markus RP (2015) Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis. Brain Struct Funct 220(2):827–840. doi:10.1007/s00429-013-0686-4

    Article  PubMed  Google Scholar 

  • Poirel VJ, Masson-Pevet M, Pevet P, Gauer F (2002) MT1 melatonin receptor mRNA expression exhibits a circadian variation in the rat suprachiasmatic nuclei. Brain Res 946(1):64–71

    Article  CAS  PubMed  Google Scholar 

  • Ramirez-Rodriguez G, Klempin F, Babu H, Benitez-King G, Kempermann G (2009) Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychopharmacology 34(9):2180–2191. doi:10.1038/npp.2009.46

    Article  CAS  PubMed  Google Scholar 

  • Ramirez-Rodriguez G, Ortiz-Lopez L, Dominguez-Alonso A, Benitez-King GA, Kempermann G (2011) Chronic treatment with melatonin stimulates dendrite maturation and complexity in adult hippocampal neurogenesis of mice. J Pineal Res 50(1):29–37. doi:10.1111/j.1600-079X.2010.00802.x

    Article  CAS  PubMed  Google Scholar 

  • Ranft K, Dobrowolny H, Krell D, Bielau H, Bogerts B, Bernstein HG (2010) Evidence for structural abnormalities of the human habenular complex in affective disorders but not in schizophrenia. Psychol Med 40(4):557–567. doi:10.1017/s0033291709990821

    Article  CAS  PubMed  Google Scholar 

  • Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Koppisepi S (2007) Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci 52:11–28

    CAS  PubMed  Google Scholar 

  • Reppert SM, Weaver DR, Ebisawa T (1994) Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13(5):1177–1185

    Article  CAS  PubMed  Google Scholar 

  • Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF (1995) Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci USA 92(19):8734–8738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reppert SM, Weaver DR, Ebisawa T, Mahle CD, Kolakowski LF Jr (1996) Cloning of a melatonin-related receptor from human pituitary. FEBS Lett 386(2–3):219–224

    Article  CAS  PubMed  Google Scholar 

  • Rivera-Bermudez MA, Masana MI, Brown GM, Earnest DJ, Dubocovich ML (2004) Immortalized cells from the rat suprachiasmatic nucleus express functional melatonin receptors. Brain Res 1002(1–2):21–27. doi:10.1016/j.brainres.2003.12.008

    Article  CAS  PubMed  Google Scholar 

  • Roy D, Belsham DD (2002) Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7 GnRH neurons. Signal transduction mechanisms. J Biol Chem 277(1):251–258. doi:10.1074/jbc.M108890200

    Article  CAS  PubMed  Google Scholar 

  • Ruksee N, Tongjaroenbuangam W, Mahanam T, Govitrapong P (2014) Melatonin pretreatment prevented the effect of dexamethasone negative alterations on behavior and hippocampal neurogenesis in the mouse brain. J Steroid Biochem Mol Biol 143:72–80. doi:10.1016/j.jsbmb.2014.02.011

    Article  CAS  PubMed  Google Scholar 

  • Saarela S, Reiter RJ (1994) Function of melatonin in thermoregulatory processes. Life Sci 54(5):295–311

    Article  CAS  PubMed  Google Scholar 

  • Sallinen P, Saarela S, Ilves M, Vakkuri O, Leppaluoto J (2005) The expression of MT1 and MT2 melatonin receptor mRNA in several rat tissues. Life Sci 76(10):1123–1134. doi:10.1016/j.lfs.2004.08.016

    Article  CAS  PubMed  Google Scholar 

  • Saravanan KS, Sindhu KM, Mohanakumar KP (2007) Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model. J Pineal Res 42(3):247–253. doi:10.1111/j.1600-079X.2006.00412.x

    Article  CAS  PubMed  Google Scholar 

  • Savaskan E, Olivieri G, Meier F, Brydon L, Jockers R, Ravid R, Wirz-Justice A, Muller-Spahn F (2002a) Increased melatonin 1a-receptor immunoreactivity in the hippocampus of Alzheimer’s disease patients. J Pineal Res 32(1):59–62

    Article  PubMed  Google Scholar 

  • Savaskan E, Wirz-Justice A, Olivieri G, Pache M, Krauchi K, Brydon L, Jockers R, Muller-Spahn F, Meyer P (2002b) Distribution of melatonin MT1 receptor immunoreactivity in human retina. J Histochem Cytochem Off J Histochem Soc 50(4):519–526. doi:10.1177/002215540205000408

    Article  CAS  Google Scholar 

  • Savaskan E, Ayoub MA, Ravid R, Angeloni D, Fraschini F, Meier F, Eckert A, Muller-Spahn F, Jockers R (2005) Reduced hippocampal MT2 melatonin receptor expression in Alzheimer’s disease. J Pineal Res 38(1):10–16. doi:10.1111/j.1600-079X.2004.00169.x

    Article  CAS  PubMed  Google Scholar 

  • Savaskan E, Jockers R, Ayoub M, Angeloni D, Fraschini F, Flammer J, Eckert A, Muller-Spahn F, Meyer P (2007) The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer’s disease. Curr Alzheimer Res 4(1):47–51

    Article  CAS  PubMed  Google Scholar 

  • Scher J, Wankiewicz E, Brown GM, Fujieda H (2002) MT(1) melatonin receptor in the human retina: expression and localization. Investig Ophthalmol Vis Sci 43(3):889–897

    Google Scholar 

  • Sharkey J, Olcese J (2007) Transcriptional inhibition of oxytocin receptor expression in human myometrial cells by melatonin involves protein kinase C signaling. J Clin Endocrinol Metab 92(10):4015–4019. doi:10.1210/jc.2007-1128

    Article  CAS  PubMed  Google Scholar 

  • Shelton L, Pendse G, Maleki N, Moulton EA, Lebel A, Becerra L, Borsook D (2012) Mapping pain activation and connectivity of the human habenula. J Neurophysiol 107(10):2633–2648. doi:10.1152/jn.00012.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata S, Cassone VM, Moore RY (1989) Effects of melatonin on neuronal activity in the rat suprachiasmatic nucleus in vitro. Neurosci Lett 97(1–2):140–144

    Article  CAS  PubMed  Google Scholar 

  • Siuciak JA, Fang JM, Dubocovich ML (1990) Autoradiographic localization of 2-[125I]iodomelatonin binding sites in the brains of C3H/HeN and C57BL/6J strains of mice. Eur J Pharmacol 180(2–3):387–390

    Article  CAS  PubMed  Google Scholar 

  • Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT (2012) Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol 351(2):152–166. doi:10.1016/j.mce.2012.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song Y, Ayre EA, Pang SF (1992) The identification and characterization of 125I-labelled iodomelatonin-binding sites in the duck kidney. J Endocrinol 135(2):353–359

    Article  CAS  PubMed  Google Scholar 

  • Song Y, Chan CW, Brown GM, Pang SF, Silverman M (1997) Studies of the renal action of melatonin: evidence that the effects are mediated by 37 kDa receptors of the Mel1a subtype localized primarily to the basolateral membrane of the proximal tubule. Faseb J 11(1):93–100

    PubMed  Google Scholar 

  • Srinivasan V, Cardinali DP, Srinivasan US, Kaur C, Brown GM, Spence DW, Hardeland R, Pandi-Perumal SR (2011) Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection. Ther Adv Neurol Disord 4(5):297–317. doi:10.1177/1756285611406166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stankov B, Cozzi B, Lucini V, Fumagalli P, Scaglione F, Fraschini F (1991) Characterization and mapping of melatonin receptors in the brain of three mammalian species: rabbit, horse and sheep. A comparative in vitro binding study. Neuroendocrinology 53(3):214–221

    Article  CAS  PubMed  Google Scholar 

  • Stankov B, Biella G, Panara C, Lucini V, Capsoni S, Fauteck J, Cozzi B, Fraschini F (1992) Melatonin signal transduction and mechanism of action in the central nervous system: using the rabbit cortex as a model. Endocrinology 130(4):2152–2159. doi:10.1210/endo.130.4.1312448

    CAS  PubMed  Google Scholar 

  • Sugden D, McArthur AJ, Ajpru S, Duniec K, Piggins HD (1999) Expression of mt(1) melatonin receptor subtype mRNA in the entrained rat suprachiasmatic nucleus: a quantitative RT-PCR study across the diurnal cycle. Brain Res Mol Brain Res 72(2):176–182

    Article  CAS  PubMed  Google Scholar 

  • Tosini G, Owino S, Guillaume JL, Jockers R (2014) Understanding melatonin receptor pharmacology: latest insights from mouse models, and their relevance to human disease. BioEssays 36(8):778–787. doi:10.1002/bies.201400017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uz T, Akhisaroglu M, Ahmed R, Manev H (2003) The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice. Neuropsychopharmacology 28(12):2117–2123. doi:10.1038/sj.npp.1300254

    CAS  PubMed  Google Scholar 

  • Uz T, Arslan AD, Kurtuncu M, Imbesi M, Akhisaroglu M, Dwivedi Y, Pandey GN, Manev H (2005) The regional and cellular expression profile of the melatonin receptor MT1 in the central dopaminergic system. Brain Res Mol Brain Res 136(1–2):45–53. doi:10.1016/j.molbrainres.2005.01.002

    Article  CAS  PubMed  Google Scholar 

  • Videnovic A, Noble C, Reid KJ, Peng J, Turek FW, Marconi A, Rademaker AW, Simuni T, Zadikoff C, Zee PC (2014) Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol 71(4):463–469. doi:10.1001/jamaneurol.2013.6239

    Article  PubMed  PubMed Central  Google Scholar 

  • von Gall C, Weaver DR, Moek J, Jilg A, Stehle JH, Korf HW (2005) Melatonin plays a crucial role in the regulation of rhythmic clock gene expression in the mouse pars tuberalis. Ann N Y Acad Sci 1040:508–511. doi:10.1196/annals.1327.105

    Article  CAS  Google Scholar 

  • Waly N, Hallworth R (2015) Circadian Pattern of melatonin MT1 and MT2 receptor localization in the rat suprachiasmatic nucleus. J Circadian Rhythms 13:Art. 1

    Article  Google Scholar 

  • Wang LM, Suthana NA, Chaudhury D, Weaver DR, Colwell CS (2005) Melatonin inhibits hippocampal long-term potentiation. Eur J Neurosci 22(9):2231–2237. doi:10.1111/j.1460-9568.2005.04408.x

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang X, Sirianni A, Pei Z, Cormier K, Smith K, Jiang J, Zhou S, Wang H, Zhao R, Yano H, Kim JE, Li W, Kristal BS, Ferrante RJ, Friedlander RM (2011) The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J Neurosci 31(41):14496–14507. doi:10.1523/jneurosci.3059-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weaver DR, Stehle JH, Stopa EG, Reppert SM (1993) Melatonin receptors in human hypothalamus and pituitary: implications for circadian and reproductive responses to melatonin. J Clin Endocrinol Metab 76(2):295–301. doi:10.1210/jcem.76.2.8381796

    CAS  PubMed  Google Scholar 

  • Weaver DR, Reppert SM (1996) The Mel1a melatonin receptor gene is expressed in human suprachiasmatic nuclei. Neuroreport 8(1):109–112

    Article  CAS  PubMed  Google Scholar 

  • Weaver DR, Liu C, Reppert SM (1996) Nature’s knockout: the Mel1b receptor is not necessary for reproductive and circadian responses to melatonin in Siberian hamsters. Mol Endocrinol 10(11):1478–1487. doi:10.1210/mend.10.11.8923472

    CAS  PubMed  Google Scholar 

  • Weil ZM, Hotchkiss AK, Gatien ML, Pieke-Dahl S, Nelson RJ (2006) Melatonin receptor (MT1) knockout mice display depression-like behaviors and deficits in sensorimotor gating. Brain Res Bull 68(6):425–429. doi:10.1016/j.brainresbull.2005.09.016

    Article  CAS  PubMed  Google Scholar 

  • Wiechmann AF, Sherry DM (2013) Role of melatonin and its receptors in the vertebrate retina. Int Rev Cell Mol Biol 300:211–242. doi:10.1016/b978-0-12-405210-9.00006-0

    Article  CAS  PubMed  Google Scholar 

  • Williams LM (1989) Melatonin-binding sites in the rat brain and pituitary mapped by in vitro autoradiography. J Mol Endocrinol 3(1):71–75

    Article  CAS  PubMed  Google Scholar 

  • Williams LM, Lincoln GA, Mercer JG, Barrett P, Morgan PJ, Clarke IJ (1997) Melatonin receptors in the brain and pituitary gland of hypothalamo-pituitary disconnected Soay rams. J Neuroendocrinol 9(8):639–643

    Article  CAS  PubMed  Google Scholar 

  • Witt-Enderby PA, Bennett J, Jarzynka MJ, Firestine S, Melan MA (2003) Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci 72(20):2183–2198

    Article  CAS  PubMed  Google Scholar 

  • Wongchitrat P, Lansubsakul N, Kamsrijai U, Sae-Ung K, Mukda S, Govitrapong P (2016) Melatonin attenuates the high-fat diet and streptozotocin-induced reduction in rat hippocampal neurogenesis. Neurochem Int 100:97–109. doi:10.1016/j.neuint.2016.09.006

    Article  CAS  PubMed  Google Scholar 

  • Wu YH, Zhou JN, Balesar R, Unmehopa U, Bao A, Jockers R, Van Heerikhuize J, Swaab DF (2006) Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone. J Comp Neurol 499(6):897–910. doi:10.1002/cne.21152

    Article  CAS  PubMed  Google Scholar 

  • Wu YH, Ursinus J, Zhou JN, Scheer FA, Ai-Min B, Jockers R, van Heerikhuize J, Swaab DF (2013) Alterations of melatonin receptors MT1 and MT2 in the hypothalamic suprachiasmatic nucleus during depression. J Affect Disord 148(2–3):357–367. doi:10.1016/j.jad.2012.12.025

    Article  CAS  PubMed  Google Scholar 

  • Yang XF, Miao Y, Ping Y, Wu HJ, Yang XL, Wang Z (2011) Melatonin inhibits tetraethylammonium-sensitive potassium channels of rod ON type bipolar cells via MT2 receptors in rat retina. Neuroscience 173:19–29. doi:10.1016/j.neuroscience.2010.11.028

    Article  CAS  PubMed  Google Scholar 

  • Yu CX, Wu GC, Xu SF, Chen CH (2000) Melatonin influences the release of endogenous opioid peptides in rat periaqueductal gray. Sheng li xue bao [Acta physiologica Sinica] 52(3):207–210

    CAS  Google Scholar 

  • Zisapel N (2001) Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting. Cell Mol Neurobiol 21(6):605–616

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by MOSTI eScience Research Grant (02-02-10-SF0109) from Ministry of Science, Technology and Innovation of Malaysia.

Author information

Authors and Affiliations

  1. School of Pharmacy, Monash University Malaysia, 47500, Subang Jaya, Selangor, Malaysia

    Khuen Yen Ng

  2. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500, Subang Jaya, Selangor, Malaysia

    Khuen Yen Ng

  3. School of Science, Monash University Malaysia, 47500, Subang Jaya, Selangor, Malaysia

    Mun Kit Leong

  4. Brain Structure and Function Group, Neuroscience Research Australia, Randwick, NSW, Australia

    Huazheng Liang & George Paxinos

  5. School of Medicine, Western Sydney University, Campbelltown, NSW, Australia

    Huazheng Liang

  6. School of Medical Sciences, The University of New South Wales, Kensington, NSW, Australia

    George Paxinos

Authors
  1. Khuen Yen Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mun Kit Leong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huazheng Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George Paxinos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Khuen Yen Ng.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ng, K.Y., Leong, M.K., Liang, H. et al. Melatonin receptors: distribution in mammalian brain and their respective putative functions. Brain Struct Funct 222, 2921–2939 (2017). https://doi.org/10.1007/s00429-017-1439-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-017-1439-6

Keywords

Search

Navigation