Skip to main content

Advertisement

Log in

Melatonin–Dopamine Interactions: From Basic Neurochemistry to a Clinical Setting

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin–dopamine interactions in mammals. Melatonin, the hormone produced by the pineal gland atnight, influences circadian and seasonal rhythms, most notably the sleep–wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears tobe effective in the treatment of tardive dyskinesia, a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D2 receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  • Adler, L. A.,Edson, R.,Lavori, P.,Peselow, E.,Duncan, E.,Rosenthal, M., andRotrosen, J. (1998). Long-term treatment effects of vitamin E for tardive dyskinesia. Biol. Psychiatry 43: 868-872.

    Google Scholar 

  • Alexiuk, N. A.,Uddin, M., andVriend, J. (1996). Melatonin increases the in situ activity of tyrosine hydroxylase in the mediobasal hypothalamus of male Syrian hamsters. Life Sci. 59: 687-694.

    Google Scholar 

  • Alexiuk, N. A., andVriend, J. P. (1993). Melatonin reduces dopamine content in the neurointermediate lobe of male Syrian hamsters. Brain Res. Bull. 32: 433-436.

    Google Scholar 

  • Barak, Y.,Swartz, M.,Shamir, E.,Stein, D., andWeizman, A. (1998). Vitamin E (alpha-tocopherol) in the treatment of tardive dyskinesia: A statistical meta-analysis. Ann. Clin. Psychiatry 10: 101-105.

    Google Scholar 

  • Cagnacci, A.,Elliott, J. A., andYen, S. S. (1992). Melatonin: A major regulator of the circadian rhythm of core temperature in humans. J. Clin. Endocrinol. Metab. 75: 447-452.

    Google Scholar 

  • Cajochen, C.,Krauchi, K.,von Arx, M. A.,Mori, D.,Graw, P., andWirz-Justice, A. (1996). Daytime melatonin administration enhances sleepiness and theta/alpha activity in the waking EEG. Neurosci. Lett. 207: 209-213.

    Google Scholar 

  • Cardoso, F., andJankovic, J. (1997). Dystonia and dyskinesia. Psychiatr. Clin. N. Am. 20: 821-838.

    Google Scholar 

  • Coon, S. L.,Roseboom, P. H.,Baler, R.,WWeller, J. L.,Namboodiri, M. A.,Koonin, E. V., andKlein, D. C. (1995). Pineal serotonin N-acetyltransferase: Expression cloning and molecular analysis. Science 270: 1681-1683.

    Google Scholar 

  • Cote, L., andCrutcher, M. (1991). The basal ganglia. In Kandel, E. R.,Scwartz, J. H., andJessel, T. M. (eds.), Principles of Neural Science, Appleton and Young, New York, pp. 647-659.

    Google Scholar 

  • Dabbeni-Sala, F.,Di Santo, S.,Franceschini, D.,Skaper, S. D., andGiusti, P. (2001). Melatonin protects against 6-OHDA-induced neurotoxicity in rats:Arole for mitochondrial complex I activity. FASEB J. 15: 164-170.

    Google Scholar 

  • Deacon, S., andArendt, J. (1996). Adapting to phase shifts, II. Effects of melatonin and conflicting light treatment. Physiol. Behav. 59: 675-682.

    Google Scholar 

  • Di Chiara, G.,Morelli, M., and Consolo, S. (1994). Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions. Trends Neurosci. 17: 228-233.

    Google Scholar 

  • Dunlap, J. C. (1999). Molecular bases for circadian clocks. Cell 96: 271-290.

    Google Scholar 

  • Ebadi, M., andGovitrapong, P. (1986). Neural pathways and neurotransmitters affecting melatonin synthesis. J. Neural. Transm. Suppl. 21: 125-155.

    Google Scholar 

  • Escames, G.,Acuna Castroviejo, D., andVives, F. (1996). Melatonin-dopamine interaction in the striatal projection area of sensorimotor cortex in the rat. Neuroreport 7: 597-600.

    Google Scholar 

  • Escames, G.,Macias, M.,Leon, J.,Garcia, J.,Khaldy, H.,Martin, M.,Vives, F., andAcuna-Castroviejo, D. (2001). Calcium-dependent effects of melatonin inhibition of glutamatergic response in rat striatum. J. Neuroendocrinol. 13: 459-466.

    Google Scholar 

  • Exposito, I.,Mora, F.,Zisapel, N., andOaknin, S. (1995). The modulatory effect of melatonin on the dopamine-glutamate interaction in the anterior hypothalamus during ageing. Neuroreport 6: 2399-2403.

    Google Scholar 

  • Forsling, M. L.,Wheeler, M. J., andWilliams, A. J. (1999). The effect of melatonin administration on pituitary hormone secretion in man. Clin. Endocrinol. (Oxf). 51: 637-542.

    Google Scholar 

  • Fujieda, H.,Scher, J.,Hamadanizadeh, S. A.,Wankiewicz, E.,Pang, S. F., andBrown, G. M. (2000). Dopaminergic and GABAergic amacrine cells are direct targets of melatonin: Immunocytochemical study of mt1 melatonin receptor in guinea pig retina. Vis. Neurosci. 17: 63-70.

    Google Scholar 

  • Garfinkel, D.,Laudon, M.,Nof, D., andZisapel, N. (1995). Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 346: 541-544.

    Google Scholar 

  • Gastel, J. A.,Roseboom, P. H.,Rinaldi, P. A.,W eller, J. L., andKlein, D. C. (1998). Melatonin production: Proteasomal proteolysis in serotonin N-acetyltransferase regulation. Science 279: 1358-1360.

    Google Scholar 

  • Grosse, J., andDavis, F. C. (1999). Transient entrainment of a circadian pacemaker during development by dopaminergic activation in Syrian hamsters. Brain Res. Bull. 48: 185-194.

    Google Scholar 

  • Hastings, M. (1998). The brain, circadian rhythms, and clock genes. BMJ. 317: 1704-1707.

    Google Scholar 

  • Hedlund, L.,Lischko, M. M.,Rollag, M.D., andNiswender, G.D. (1977). Melatonin: Daily cycle in plasma and cerebrospinal fluid of calves. Science 195: 686-687.

    Google Scholar 

  • Hunt, A. E.,Al-Ghoul, W. M.,Gillette, M. U., andDubocovich, M. L. (2001). Activation of MT(2) melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am.J. Physiol. Cell Physiol. 280: C110-C118.

    Google Scholar 

  • Jaliffa, C. O.,Lacoste, F. F.,Llomovatte, D.W.,Sarmiento, M. I., andRosenstein, R. E. (2000). Dopamine decreases melatonin content in golden hamster retina. J. Pharmacol. Exp. Ther. 293: 91-95.

    Google Scholar 

  • Joo, W. S.,Jin, B. K.,Park, C. W.,Maeng, S. H., andKim, Y. S. (1998). Melatonin increases striatal dopaminergic function in 6-OHDA-lesioned rats. Neuroreport 9: 4123-4126.

    Google Scholar 

  • Kim, Y. S.,Joo, W. S.,Jin, B. K.,Cho, Y. H.,Baik, H. H., andPark, C. W. (1998). Melatonin protects 6-OHDA-induced neuronal death of nigrostriatal dopaminergic system. Neuroreport 9: 2387-2390.

    Google Scholar 

  • Krauchi, K.,Cajochen, C.,Werth, E., andWirz-Justice, A. (2000). Functional link between distal vasodilation and sleep-onset latency? Am. J. Physiol. Regul. Integr. Comp. Physiol. 278: R741-R748.

    Google Scholar 

  • Laudon, M., andZisapel, N. (1986). Characterization of central melatonin receptors using 125I-melatonin. FEBS Lett. 197: 9-12.

    Google Scholar 

  • Leon, J.,Vives, F.,Crespo, E.,Camacho, E.,Espinosa, A.,Gallo, M. A.,Escames, G., andAcuna-Castroviejo, D. (1998). Modification of nitric oxide synthase activity and neuronal response in rat striatum by melatonin and kynurenine derivatives. J. Neuroendocrinol. 10: 297-302.

    Google Scholar 

  • Lewy, A. J.,Ahmed, S.,Jackson, J. M., andSack, R. L. (1992). Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol. Int. 9: 380-392.

    Google Scholar 

  • Lewy, A. J.,Ahmed, S., andSack, R. L. (1996). Phase shifting the human circadian clock using melatonin. Behav. Brain Res. 73: 131-134.

    Google Scholar 

  • Lincoln, G. (1999). Melatonin modulation of prolactin and gonadotrophin secretion. Systems ancient and modern. Adv. Exp. Med. Biol. 460: 137-153.

    Google Scholar 

  • Liu, C.,Weaver, D. R.,Jin, X.,Shearman, L. P.,Pieschl, R. L.,Gribkoff, V. K., andReppert, S. M. (1997). Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19: 91-102.

    Google Scholar 

  • Lockley, S. W.,Skene, D. J.,Tabandeh, H.,Bird, A. C.,Defrance, R., andArendt, J. (1997). Relationship between napping and melatonin in the blind. J. Biol. Rhythms 12: 16-25.

    Google Scholar 

  • McArthur, A. J.,Hunt, A. E., andGillette, M. U. (1997). Melatonin action and signal transduction in the rat suprachiasmatic circadian clock: Activation of protein kinase C at dusk and dawn. Endocrinology 138: 627-634.

    Google Scholar 

  • Misztal, T.,Romanowicz, K., andBarcikowski, B. (1997). Natural and melatonin-stimulated changes in the circadian rhythm of prolactin secretion in the ewe during seasonal anestrus. Neuroendocrinology 66: 360-367.

    Google Scholar 

  • Naitoh, N.,Watanabe, Y.,Matsumura, K.,Murai, I.,Kobayashi, K.,Imai-Matsumura, K.,Ohtuka, H.,Takagi, K.,Miyake, Y., andSatoh, K. (1998). Alteration by maternal pinealectomy of fetal and neonatal melatonin and dopamine D1 receptor binding in the suprachiasmatic nuclei. Biochem. Biophys. Res. Commun. 253: 850-854.

    Google Scholar 

  • Nosjean, O.,Ferro, M.,Coge, F.,Beauverger, P.,Henlin, J. M.,Lefoulon, F.,Fauchere, J. L.,Delagrange, P.,Canet, E., andBoutin, J. A. (2000). Identification of the melatonin-binding site MT3 as the quinone reductase 2. J. Biol. Chem. 275: 31311-31317.

    Google Scholar 

  • Ortiz, G.G.,Crespo-Lopez, M. E.,Moran-Moguel, C.,Garcia, J. J.,Reiter,R. J., andAcuna-Castroviejo, D. (2001). Protective role of melatonin against MPTP-induced mouse brain cell DNA fragmentation and apoptosis in vivo. Neuroendocrinol. Lett. 22: 101-108.

    Google Scholar 

  • Pai, B. N.,Janakiramaiah, N.,Gangadhar, B. N., andRavindranath, V. (1994). Depletion of glutathione and enhanced lipid peroxidation in the CSF of acute psychotics following haloperidol administration. Biol. Psychiatry 36: 489-491.

    Google Scholar 

  • Post, A.,Holsboer, F., andBehl, C. (1998). Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: Suppression of NF-kappaB and neuroprotection by antioxidants. J. Neurosci. 18: 8236-8246.

    Google Scholar 

  • Rao,M. L.,Gross, G.,Strebel, B.,Braunig, P.,Huber, G., andKlosterkotter, J. (1990). Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects. Psychiatry Res. 34: 243-257.

    Google Scholar 

  • Reiter, R. J. (1991). Pineal melatonin: Cell biology of its synthesis and of its physiological interactions. Endocr. Rev. 12: 151-180.

    Google Scholar 

  • Reppert, S. M. (1997). Melatonin receptors: Molecular biology of a new family of G protein-coupled receptors. J. Biol. Rhythms 12: 528-531.

    Google Scholar 

  • Rivest, R. W.,Aubert, M. L.,Lang, U., andSizonenko, P. C. (1986). Puberty in the rat: Modulation by melatonin and light. J. Neural. Transm. Suppl. 21: 81-108.

    Google Scholar 

  • Rousseau, A.,Petren, S.,Plannthin, J.,Eklundh, T., andNordin, C. (1999). Serum and cerebrospinal fluid concentrations of melatonin:Apilot study in healthy male volunteers. J. Neural.Transm. 106: 883-888.

    Google Scholar 

  • Schapira, A. H. (2001). Causes of neuronal death in Parkinson's disease. Adv. Neurol. 86: 155-162.

    Google Scholar 

  • Shamir, E.,Barak, Y.,Plopsky, I.,Zisapel, N.,Elizur, A., andWeizman, A. (2000). Is melatonin treatment effective for tardive dyskinesia? J. Clin. Psychiatry 61: 556-558.

    Google Scholar 

  • Shamir, E.,Barak, Y.,Shalman, I.,Laudon, M.,Zisapel, N.,Tarrasch, R.,Elizur, A., andWeizman, R. (2001). Melatonin treatment for tardive-dyskinesia: A double-blind placebo-controlled cross-over study. Arch. Gen. Psychiatry 58: 1049-1052.

    Google Scholar 

  • Shieh, K. R.,Chu, Y. S., andPan, J. T. (1997). Circadian change of dopaminergic neuron activity: Effects of constant light and melatonin. Neuroreport 8: 2283-2287.

    Google Scholar 

  • Tenn, C. C., andNiles, L. P. (1997). Mechanisms underlying the antidopaminergic effect of clonazepam and melatonin in striatum. Neuropharmacology 36: 1659-1663.

    Google Scholar 

  • Tosini, G., andDirden, J. C. (2000). Dopamine inhibits melatonin release in the mammalian retina: In vitro evidence. Neurosci. Lett. 286: 119-122.

    Google Scholar 

  • Vigano, D.,Lissoni, P.,Rovelli, F.,Roselli, M. G.,Malugani, F.,Gavazzeni, C.,Conti, A., andMaestroni, G. (2001). A study of light/dark rhythm of melatonin in relation to cortisol and prolactin secretion in schizophrenia. Neuroendocrinol. Lett. 22: 137-141.

    Google Scholar 

  • Viguie, C.,Thibault, J.,Thiery, J. C.,Tillet, Y., andMalpaux, B. (1997). Characterization of the short dayinduced decrease in median eminence tyrosine hydroxylase activity in the ewe: Temporal relationship to the changes in luteinizing hormone and prolactin secretion and short day-like effect of melatonin. Endocrinology 138: 499-506.

    Google Scholar 

  • Waldhauser, F.,Boepple, P. A.,Schemper, M.,Mansfield, M. J., andCrowley, W. F., Jr. (1991). Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children. J. Clin. Endocrinol. Metab. 73: 793-796.

    Google Scholar 

  • Waldhauser, F.,Waldhauser, M.,Lieberman, H. R.,Deng,M. H.,Lynch, H. J.,andWurtman, R. J. (1984). Bioavailability of oral melatonin in humans. Neuroendocrinology 39: 307-313.

    Google Scholar 

  • Weaver, D. R.,Liu, C., andReppert, S. M. (1996). Nature's knockout: The Mel1b receptor is not necessary for reproductive and circadian responses to melatonin in Siberian hamsters. Mol. Endocrinol. 10: 1478-1487.

    Google Scholar 

  • Willis, G. L., andArmstrong, S. M. (1999). A therapeutic role for melatonin antagonism in experimental models of Parkinson's disease. Physiol. Behav. 66: 785-795.

    Google Scholar 

  • Young, S. N. (1996). Melatonin, sleep, aging, and the health protection branch. J. Psychiatry Neurosci. 21: 161-164.

    Google Scholar 

  • Zimmermann, R. C.,Krahn, L. E.,Klee, G. G.,Ditkoff, E. C.,Ory, S. J., andSauer, M. V. (2001). Prolonged inhibition of presynaptic catecholamine synthesis with alpha-methyl-para-tyrosine attenuates the circadian rhythm of human TSH secretion. J. Soc. Gynecol. Invest. 8: 174-178.

    Google Scholar 

  • Zisapel, N. (1999). The use of melatonin for the treatment of insomnia. Biol. Signals Recept. 8: 84-89.

    Google Scholar 

  • Zisapel, N. (2001). Circadian rhythm sleep disorders: Pathophysiology and potential approaches to management. CNS Drugs 15: 311-428.

    Google Scholar 

  • Zisapel, N.,Egozi, Y., andLaudon, M. (1982). Inhibition of dopamine release by melatonin: Regional distribution in the rat brain. Brain Res. 246: 161-163.

    Google Scholar 

  • Zisapel, N.,Egozi, Y., andLaudon, M. (1985). Circadian variations in the inhibition of dopamine release from adult and newborn rat hypothalamus by melatonin. Neuroendocrinology 40: 102-108.

    Google Scholar 

  • Zisapel, N., andLaudon, M. (1982). Dopamine release induced by electrical field stimulation of rat hypothalamus in vitro: Inhibition by melatonin. Biochem. Biophys. Res. Commun. 104: 1610-1616.

    Google Scholar 

  • Zisapel, N., andLaudon, M. (1983). Inhibition by melatonin of dopamine release from rat hypothalamus: Regulation of calcium entry. Brain Res. 272: 378-381.

    Google Scholar 

  • Zisapel, N.,Nir, I., andLaudon, M. (1988). Circadian variations in melatonin-binding sites in discrete areas of the male rat brain. FEBS Lett. 232: 172-176.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zisapel, N. Melatonin–Dopamine Interactions: From Basic Neurochemistry to a Clinical Setting. Cell Mol Neurobiol 21, 605–616 (2001). https://doi.org/10.1023/A:1015187601628

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015187601628

Navigation