Skip to main content
Log in

Central melatonin receptors: Implications for a mode of action

  • Multi-author Review
  • Published:
Experientia Aims and scope Submit manuscript

Summary

The influence of melatonin on circadian and photoperiodic functions in numerous species is well documented. It is known that the effect of melatonin on circadian rhythmicity is mediated via the suprachiasmatic nucleus (SCN), the biological clock of the brain. It is not known however where the photoperiodic effects of melatonin are mediated. Evidence from brain lesioning and melatonin implant studies point to a site in or near the medial hypothalamus. In contrast to these studies, melatonin receptors have been reported in widespread areas of the brain, the pituitary and in peripheral tissues. The characteristics of the reported melatonin receptors vary widely between studies and consequently no definitive description of a physiologically relevant melatonin receptor has received universal recognition. This review marshals recent evidence for the localization and characterization of the melatonin receptor and discusses these findings in the context of the known effects of the hormone in different species.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Literature

  1. Arendt, J., Role of the pineal gland and melatonin in seasonal reproductive function in mammals, in: Oxford Reviews of Reproductive Biology, vol. 8, p. 266–320. Ed. G. R. Clarke. Clarendon Press, Oxford 1986.

    Google Scholar 

  2. Arendt, J., Symons, A. M., and Laud, C., Pineal function in the sheep: evidence for a possible mechanism mediating seasonal reproductive activity. Experientia37 (1981) 584–586.

    Article  CAS  PubMed  Google Scholar 

  3. Armstrong, S. M., Cassone, V. M., Chesworth, M. G., Redman, J. R., and Short, R. V., Synchronization of mammalian circadian rhythms by melatonin. J. neural Transm. [Suppl.]21 (1986) 375–394.

    CAS  Google Scholar 

  4. Berria, M., DeSantis, M., and Mead, R. A., Effects of suprachiasmatic nuclear ablation and melatonin on delayed implantation in the spotted skunk. Neuroendocrinology48 (1988) 371–375.

    Article  CAS  PubMed  Google Scholar 

  5. Bittman, E. L., and Karsch, F. J., Nightly duration of pineal melatonin secretion determining the reproductive response to inhibitory daylength in the ewe. Biol. Reprod.30 (1984) 585–593.

    Article  CAS  PubMed  Google Scholar 

  6. Bittman, E. L., Goldman, B. D., and Zucker, I., Testicular responses to melatonin are altered by lesions of the suprachiasmatic nuclei in golden hamster. Biol. Reprod.21 (1979) 647–656.

    Article  CAS  PubMed  Google Scholar 

  7. Bittman, E. L., Dempsey, R. L., and Karsch, F. J., Pineal melatonin secretion drives the reproductive response to daylength in the ewe. Endocrinology113 (1983) 2276–2288.

    Article  CAS  PubMed  Google Scholar 

  8. Bubenik, G. A., Brown, G. M., Uhlir, G., and Grota, L. G., Immunohistological localization of N-acetylindolealkylamines in pineal gland, retina and cerebellum. Brain Res.81 (1974) 223–242.

    Article  Google Scholar 

  9. Cahil, G. M., and Besharse, J. C., Retinal melatonin is metabolized within the eye ofXenopus laevis. Proc. natl Acad. Sci.86 (1989) 1098–1102.

    Article  Google Scholar 

  10. Cardinali, D. P., Vacas, M. I., and Boyer, E. E., Specific binding of melatonin in bovine brain. Endocrinology105 (1979) 437–441.

    Article  CAS  PubMed  Google Scholar 

  11. Carter, D. S., and Goldman, B. D., Antigonadal effects of timed melatonin infusion in pinealectomized male Djungarian hamsters (Phodopus sungorus sungorus): Duration is the critical parameter. Endocrinology113 (1983) 1261–1267.

    Article  CAS  PubMed  Google Scholar 

  12. Cassone, V. M., Roberts, M. H., and Moore, R. Y., Melatonin inhibits metabolic activity in the rat suprachiasmatic nuclei. Neurosci. Lett.81 (1987) 29–34.

    Article  CAS  PubMed  Google Scholar 

  13. Cohen M., Roselle, D., Chabner, B., Schmidt, T. J., and Lippman, M., Evidence for a cytoplasmic melatonin receptor. Nature274 (1978) 894–895.

    Article  CAS  PubMed  Google Scholar 

  14. Delmann, M.-D., Stoeckel, M.-E., Hindelang-Gertner, C., Porte, A., and Stutinsky, F., A comparative ultrastructural study of the pars tuberalis of various mammals, the chicken and the newt. Cell Tissue Res.148 (1974) 313–329.

    Article  Google Scholar 

  15. Dowell, S. F., and Lynch, G. R., Duration of the melatonin pulse in the hypothelamus controls testicular function in pinealectomized mice (Peromyscus leucopus). Biol. Reprod.36 (1987) 1095–1101.

    Article  CAS  PubMed  Google Scholar 

  16. Dubocovich, M. L., Characterization of a retinal melatonin receptor. J. Pharmac. exp. Ther.234 (1985) 395–401.

    CAS  Google Scholar 

  17. Dubocovich, M. L., Luzindole (N-0774) antagonized the melatonin-induced inhibition of3H-dopamine from rabbit retina. Soc. Neurosci. Abstr. 2904 (1987) p. 1038.

    Google Scholar 

  18. Dubocovich, M. L., Pharmacology and function of melatonin receptors. FASEB J.2 (1988) 2765–2773.

    Article  CAS  PubMed  Google Scholar 

  19. Dubocovich, M. L., and Takahashi, J. S., Use of 2-[125I]-iodomelatonin to characterize melatonin binding sites in chicken retina. Proc. natl Acad. Sci. USA84 (1987) 3916–3920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Duncan, M. J., Takahashi, J. S., and Dubocovich, M. L., 2-[125I]-iodomelatonin binding sites in hamster brain membranes: pharmacological characteristics and regional distribution.112 (1988) 1825–1833.

  21. Ellis, G. B., and Turek, F. W., Photoperiodic regulation of serum luteinizing hormone and follicle-stimulating hormone in castrated and castrated-adrenalectomized male hamsters. Endocrinology106 (1980) 1338–1344.

    Article  CAS  PubMed  Google Scholar 

  22. English, J., and Arendt, J., Characterization and circadian rhythmicity of a melatonin binding site in the rat hypothalamus. J. Reprot. Fert. Abstract Series No. 1 (1988) Abst. 6.

  23. Glass, J. D., and Lynch, G. R., Melatonin: identification of sites of antigonadal action in mouse brain. Science214 (1981) 821–823.

    Article  CAS  PubMed  Google Scholar 

  24. Glass, J. D., and Lynch, G. R., Evidence for a brain site of melatonin action in the white-footed mousePeromyscus leucopus. Neuroendocrinology34 (1982) 1–6.

    Article  CAS  PubMed  Google Scholar 

  25. Goldman, B. D., Darrow, J. M., and Yogev, L., Effects of timed melatonin infusions on reproductive development in the Djungarian hamster (Phodopus sungorus). Endocrinology114 (1984) 2074–2083.

    Article  CAS  PubMed  Google Scholar 

  26. Gross, D. S., The mammalian hypophyseal pars tuberalis: a comparative immunocytochemical study. Gen. comp. Endocr.56 (1984) 283–298.

    Article  CAS  PubMed  Google Scholar 

  27. Hastings, M. H., Walker, A. P., Roberts, A. C., and Herbert, J., Intrahypothalamic melatonin blocks photoperiodic responsiveness in the male Syrian hamster. Neuroscience24 (1988) 987–991.

    Article  CAS  PubMed  Google Scholar 

  28. Heward, C. G., and Hadley, M. E., Structure-activity relationships of melatonin and related indoleamines. Life Sci.17 (1975) 1167–1178.

    Article  CAS  PubMed  Google Scholar 

  29. Illnerova, H., Hoffman, K., and Vanecek, J., Adjustment of pineal melatonin and N-acetyltransferase rhythms to change from long to short photoperiod in the Djungarian hamster (Phodopus sungorus). Neuroendocrinology38 (1984) 226–231.

    Article  CAS  PubMed  Google Scholar 

  30. Jennes, L., and Stumpf, W. E., LH-RH systems in the brain of the golden hamster. Cell Tissue Res.209 (1980) 239–256.

    Article  CAS  PubMed  Google Scholar 

  31. Jones, E. G., The Thalamus. Plenum Press, New York 1985.

    Chapter  Google Scholar 

  32. Joss, J. M. P., Autoradiographic localisation of sites of uptake of [3H]-melatonin in the brain of the lizard and a lamprey in: Pineal Function, p. 223–234. Eds C. D. Mathews and R. F. Seamark. Elsevier/North Holland Biomedical Press, Amsterdam 1981.

    Google Scholar 

  33. Karsch, F. J., Bittman, E. L., Foster, D. L., Goodman, R. L., Legan, S. J., and Robinson, J. E., Neuroendocrine basis of seasonal reproduction. Rec. Prog. Horm. Res.40 (1984) 185–232.

    CAS  PubMed  Google Scholar 

  34. Karsch, F. J., Malpaux, B., Wayne, N. L., and Robinson, J. E., Characteristics of the melatonin signal that provide the photoperiodic code for timing seasonal reproduction in the ewe. Reprod. Nutr. Develop.28 2B (1988) 459–472.

    Article  CAS  Google Scholar 

  35. Kennaway, D. J., Sanford, L. M., Godfrey, B., and Friesen, H. G., Patterns of progesterone, melatonin and prolactin secretion in ewes maintained in four different photoperiods. J. Endocr.97 (1983) 220–242.

    Article  Google Scholar 

  36. Kuhar, M. G., Receptor localization with the microscope, in: Neurotransmitter Receptor Binding, p. 153–176. Ed. H. J. Yamamura. Raven Press, New York 1985.

    Google Scholar 

  37. Laitinen, J. T., Castre, E., Vakkuri, O., and Saavedra, J. M., Diurnal rhythm of melatonin binding in the rat suprachiasmatic nucleus. Endocrinology124 (1989) 1585–1587.

    Article  CAS  PubMed  Google Scholar 

  38. Laudon, M., and Zisapel, N., Characterization of central melatonin receptors using [125I]-melatonin. FEBS Lett.197 (1986) 9–12.

    Article  CAS  PubMed  Google Scholar 

  39. Laudon, M., and Zisapel, N., Impact of circulating estradiol on melatonin binding sites in discrete areas of the female rat brain. Brain Res.402 (1987) 146–150.

    Article  CAS  PubMed  Google Scholar 

  40. Laudon, M., Yaron, Z., and Zisapel, N., N-(3,5-dinitrophenyl)-5-methoxy-tryptamine, a novel melatonin antagonist: effects on sexual maturation of the male and female rat and on oestrous cycles of the female rat. J. Endocr.116 (1988) 43–53.

    Article  CAS  PubMed  Google Scholar 

  41. Lincoln, G. A., and Kelly, R. W., Test of a putative melatonin antagonist in the ram. J. Reprod. Fert.1 (1988) abst. 27.

    Google Scholar 

  42. Lincoln, G. A., and Short, R. V., Seasonal breeding: Nature's contraceptive. Rec. Prog. Horm. Res.36 (1980) 1–52.

    CAS  PubMed  Google Scholar 

  43. Maywood, E., Bonnefond, C., Herbert, J., and Hastings, M., Effect of hypothalamic lesions on the gonadal response to programmed melatonin infusions in the Syrian hamster. J. Endocr.121 (suppl.) (1989) abst. 158.

    Google Scholar 

  44. McMillen, I. C., and Nowak, R., Maternal pinealectomy abolishes the diurnal rhythm in plasma melatonin concentrations in the fetal sheep. J. Reprod. Fert.1 (1988) abstr. 28.

    Google Scholar 

  45. Messenger, E. A., and Warner, A. E., The action of melatonin on single amphibian pigment cells in tissue culture. Br. J. Pharmac.61 (1977) 607–614.

    Article  CAS  Google Scholar 

  46. Moore, R. Y., The suprachiasmatic nucleus and the organisation of a circadian system. TINS Nov. (1982) 404–407.

  47. Morgan, P. J., Williams, L. M., Davidson, G., Lawson, W., and Howell, E., Melatonin receptors on ovine pars tuberalis: Characterization and autoradiographical localization. J. Neuroendocr.1 (1989) 1–4.

    Article  CAS  Google Scholar 

  48. Munson, P. J., LIGAND: A computerized analysis of ligand binding data. Meth. Enzymol.92 (1984) 543–576.

    Article  Google Scholar 

  49. Niles, L. P., Pickering, D. S., and Sayer, B. G., HPLC-purified 2-[125I]-iodomelatonin labels multiple binding sites in hamster brain. Biochem. biophys. Res. Commun.147 (1987) 949–956.

    Article  CAS  PubMed  Google Scholar 

  50. Niles, L. P., Wong, Y.-W., Mishra, R. K., and Brown, G. M., Melatonin receptors in brain. Eur. J. Pharmac.55 (1979) 219–220.

    Article  CAS  Google Scholar 

  51. Redman, G., Armstrong, S., and Ng, K. T., Free-running activity rhythms in the rat: Entrainment by melatonin. Science219 (1983) 1089–1091.

    Article  CAS  PubMed  Google Scholar 

  52. Reiter, R. J., The pineal and its hormones in the control of reproduction in mammals, Endocr. Rev.1 (1980) 109–131.

    Article  CAS  PubMed  Google Scholar 

  53. Reppert, S. M., Weaver, D. R., Rivkees, S. A., and Stopa, E. G., Putative melatonin receptors in a human biological clock. Science242 (1988) 78–80.

    Article  CAS  PubMed  Google Scholar 

  54. Robbins, T. W., Hunger, in: Neuroendocrinology, p. 252–301. Eds S. L. Lightman and B. G. Everitt. Blackwell Scientific Publications, Oxford 1986.

    Google Scholar 

  55. Roberts, M. H., Cassone, V. M., and Moore R. Y., Effects of melatonin on suprachiasmatic nucleus metabolism in rats. Soc. Neurosci. Abstr.2903 (1987) p. 1038.

    Google Scholar 

  56. Roberts, A. C., Martensz, N. D., Hastings, M. H., and Herbert, J. Changes in photoperiod alter the daily rhythms of pineal melatonin content and hypothalamic β-endorphin contents and the luteinizing hormone response to naloxone in the male Syrian hamster. Endocrinology117 (1985) 141–148.

    Article  CAS  PubMed  Google Scholar 

  57. Robinson, J. E., and Karsch, F. J., Timing the breeding season of the ewe: what is the role of daylength. Reprod. Nutr. Develop.28 (1988) 387–398.

    Article  Google Scholar 

  58. Rollag, M. D., O'Callaghan, P. L., and Niswender, G. D., Serum melatonin concentrations during different stages of the animal reproductive cycle in ewes. Biol. Reprod.18 (1978) 279–285.

    Article  CAS  PubMed  Google Scholar 

  59. Scatchard, G., The atractions of proteins for small molecules and ions. Ann. NY Acad. Sci.51 (1959) 660–672.

    Article  Google Scholar 

  60. Stoeckel, M.-E., and Porte, A., Fine structure and development of the pars tuberalis in mammals, in: Ultrastructure of Endocrine Cells and Tissues, p. 29–39. Ed. P. M. Motta. Martinus Nijhoff, Boston 1984.

    Chapter  Google Scholar 

  61. Sugden, D., Melatonin analogues induced pigment granule condensation in isolatedXenopus laevis melanophores in tissue culture. J. Endocr.120 (1989) R1-R3.

    Article  CAS  PubMed  Google Scholar 

  62. Vakkuri, O., Leppaluoto, J., and Vuolteenaho, O., Development and validation of a melatonin radioimmunoassay using radioiodinated melatonin tracer. Acta endocr.106 (1984) 152–157.

    CAS  PubMed  Google Scholar 

  63. Vakkuri, O., Lamsa E., Rahkamaa, E., Ruotsalainen, H., and Leppaluoto, J., Iodinated melatonin: preparation and characterization of the molecular structure by mass or1H NMR spectroscopy. Analyt. Biochem.142 (1984) 284–289.

    Article  CAS  PubMed  Google Scholar 

  64. Vanecek, J., Melatonin binding sites. J. Neurochem.51 (1988) 1436–1440.

    Article  CAS  PubMed  Google Scholar 

  65. Vanecek, J., The melatonin receptors in rat ontogenesis. Neuroendocrinology48 (1988) 201–203.

    Article  CAS  PubMed  Google Scholar 

  66. Vanecek, J., and Jansky, L., Short days induce changes in specific melatonin binding in hamster median eminence and anterior pituitary. Brain Res.477 (1989) 387–390.

    Article  CAS  PubMed  Google Scholar 

  67. Vanecek, J., Pavlik, A., and Illnerova, H., Hypothalamic melatonin receptor sites revealed by autoradiography. Brain Res.435 (1987) 359–363.

    Article  CAS  PubMed  Google Scholar 

  68. Watts, A. G., Swanson, L. W., Sanches-Watts, G., Efferent projections of the suprachiasmatic nucleus: 1. Studies using the anterograde transport ofPhaseolus vulgaris leucoagglutinin in the rat. J. comp. Neurol.258 (1987) 204–229.

    Article  CAS  PubMed  Google Scholar 

  69. Watts, A. G., and Swanson, L. W., Efferent projections of the suprachiasmatic nucleus. II. Studies using retrograde transport of fluorescent dyes and simultaneous peptide immunocytochemistry in the rat. J. comp. Neurol.258 (1987) 230–252.

    Article  CAS  PubMed  Google Scholar 

  70. Watts, A. G., Sheward, W. G., Whale, D., and Fink, G., The effect of knife cuts in the sub-paraventricular zone of the female rat hypothalamus on the oestrogen induced diurnal surges of plasma prolactin and lutienizing hormone and circadian wheel running activity. J. Endocr. (1989) in press.

  71. Weaver, D. R., and Reppert, S. M., Maternal melatonin communicates daylength to the fetus in Djungarian hamsters. Endocrinology119 (1986) 2861–2863.

    Article  CAS  PubMed  Google Scholar 

  72. Weaver D. R., Keohma, J., and Reppert, S. M., Maternal fetal communication of circadian phase in a precocius rodent the spiny mouse. Am. J. Physiol.253 (1987) E401–404.

    CAS  PubMed  Google Scholar 

  73. Weaver, D. R., Namboodiri, M. A. A., and Reppert, S. M., Iodinated melatonin mimics melatonin action and reveals discrete binding sites in fetal brain. FEBS Lett.228 (1988) 123–127.

    Article  CAS  PubMed  Google Scholar 

  74. Weaver, D. R., Rivkees, S. A., and Reppert, S. M., Autoradiographic localization of iodomelatonin binding sites in the hypothalamus of three rodent species. Endocr. Soc. Abst.177 (1988) 265.

    Google Scholar 

  75. Weichmann, A. F., Melatonin: Parallels in pineal gland and retina. Exp. Eye Res.42 (1986) 507–527.

    Article  Google Scholar 

  76. Weichmann, A. F., Bok, D., and Horwitz, J., Melatonin-binding in the frog retina. Autoradiographic and biochemical analysis. Invest. Ophthalmol. vis. Sci.27 (1986) 153–163.

    Google Scholar 

  77. Williams, L. M., Melatonin binding sites in the rat brain and pituitary mapped by in vitro autoradiography. J. molec. Endocr.3 (1989) 71–75.

    Article  CAS  Google Scholar 

  78. Williams, L. M., Hastings, M. H., and Morgan, P. J., Localization of melatonin binding sites by in vitro autoradiography in the brain of the Syrian hamster and the effect of neurone specific lesions. J. Endocr.119 (1988) Abst. 79.

  79. Williams, L. M., and Morgan, P. J., Demonstration of melatonin-binding sites of the pars tuberalis of the rat. J. Endocr.119 (1988) R1-R3.

    Article  CAS  PubMed  Google Scholar 

  80. Williams, L. M., Morgan, P. J., Hastings, M. H., Lawson, W., Davidson, G., and Howell, H. E., Melatonin receptor sites in the Syrian hamster brain and pituitary. Localization and characterization using [125I] iodomelatonin. J. Neuroendocr.1 (1989) 1–4.

    Article  Google Scholar 

  81. Wittkowski, W., Bergmann, M., Hoffman, K., and Pera, F., Photoperiod-dependent changes in TSH-like immunoreactivity of cells in the hypophysial pars tuberalis of the Djungarian hamsterPhodopus sungorus. Cell Tissue Res.251 (1988) 183–187.

    Article  CAS  PubMed  Google Scholar 

  82. Wittkowski, W., Hewing, M., Hoffman, K., Bergmann, M., and Fechner, J., Influence of photoperiod on the ultrastructure of the hypophysical pars tuberalis of the Djungarian hamsterPhodopus sungorus. Cell Tissue Res.238 (1984) 213–216.

    Article  CAS  PubMed  Google Scholar 

  83. Yellon, S. M., Bittman, E. L., Lehman, M. N., Olster, D. H., Robinson, J. E., and Karsch, F. J., Importance of duration of nocturnal melatonin secretion in determining the reproductive response to inductive photoperiod in the ewe. Biol. Reprod.32 (1985) 523–529.

    Article  CAS  PubMed  Google Scholar 

  84. Yellon, S. M., and Longo, L. D., Melatonin rhythms in fetal and maternal circulation during pregnancy in sheep. Am. J. Physiol.252 (1987) E799–802.

    CAS  PubMed  Google Scholar 

  85. Zemdegs, I. Z., McMillen, I. C., Walker, D. W., Thorburn, G. D., and Novak, R., Diurnal rhythms in plasma melatonin concentrations in the fetal sheep and pregnant ewe during late gestation. Endocrinology234 (1988) 284–289.

    Article  Google Scholar 

  86. Zisapel, N., Melatonin receptors revisited. J. neural Transm.73 (1988) 1–5.

    Article  CAS  PubMed  Google Scholar 

  87. Zisapel, N., and Laudon, M., A novel melatonin antagonist affects melatonin-mediated processes in vitro and in vivo. Eur. J. Pharmac.136 (1987) 259–260.

    Article  CAS  Google Scholar 

  88. Zisapel, N., Egozi, V., and Laudon, M., Circadian variations in the inhibition of dopamine release from adult and newborn rat hypothalamus by melatonin. Neuroendocrinology40 (1985) 102–108.

    Article  CAS  PubMed  Google Scholar 

  89. Zisapel, N., Shaharabani, M., and Laudon, M., Regulation of melatonin's activity in the female rat brain by estradiol: effects of neurotransmitter release and on iodomelatonin binding sites. Neuroendocrinology46 (1987) 207–216.

    Article  CAS  PubMed  Google Scholar 

  90. Zisapel, N., and Anis, Y., Impact of circulating testosterone on iodomelatonin binding sites in the male rat brain. J. molec. cell. Endocr.60 (1989) 119–1267.

    Article  Google Scholar 

  91. Zisapel, N., Nir, J., and Laudon, M., Circadian variations in melatonin-binding sites in discrete areas of the male rat brain. FEBS Lett.232 (1988) 172–176.

    Article  CAS  PubMed  Google Scholar 

  92. Zisapel, N., Erratum, J. Endocr.118 (1988) 168.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morgan, P.J., Williams, L.M. Central melatonin receptors: Implications for a mode of action. Experientia 45, 955–965 (1989). https://doi.org/10.1007/BF01953053

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01953053

Key words

Navigation