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Research ArticleArticle

Melatonin Supports CYP2D-Mediated Serotonin Synthesis in the Brain

Anna Haduch, Ewa Bromek, Jacek Wójcikowski, Krystyna Gołembiowska and Władysława A. Daniel
Drug Metabolism and Disposition March 2016, 44 (3) 445-452; DOI: https://doi.org/10.1124/dmd.115.067413
Anna Haduch
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
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Ewa Bromek
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
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Jacek Wójcikowski
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
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Krystyna Gołembiowska
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
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Władysława A. Daniel
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
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Abstract

Melatonin is used in the therapy of sleep and mood disorders and as a neuroprotective agent. The aim of our study was to demonstrate that melatonin supported (via its deacetylation to 5-methoxytryptamine) CYP2D-mediated synthesis of serotonin from 5-methoxytryptamine. We measured serotonin tissue content in some brain regions (the cortex, hippocampus, nucleus accumbens, striatum, thalamus, hypothalamus, brain stem, medulla oblongata, and cerebellum) (model A), as well as its extracellular concentration in the striatum using an in vivo microdialysis (model B) after melatonin injection (100 mg/kg i.p.) to male Wistar rats. Melatonin increased the tissue concentration of serotonin in the brain structures studied of naïve, sham-operated, or serotonergic neurotoxin (5,7-dihydroxytryptamine)–lesioned rats (model A). Intracerebroventricular quinine (a CYP2D inhibitor) prevented the melatonin-induced increase in serotonin concentration. In the presence of pargyline (a monoaminoxidase inhibitor), the effect of melatonin was not visible in the majority of the brain structures studied but could be seen in all of them in 5,7-dihydroxytryptamine–lesioned animals when serotonin storage and synthesis via a classic tryptophan pathway was diminished. Melatonin alone did not significantly increase extracellular serotonin concentration in the striatum of naïve rats but raised its content in pargyline-pretreated animals (model B). The CYP2D inhibitor propafenone given intrastructurally prevented the melatonin-induced increase in striatal serotonin in those animals. The obtained results indicate that melatonin supports CYP2D-catalyzed serotonin synthesis from 5-methoxytryptamine in the brain in vivo, which closes the serotonin-melatonin-serotonin biochemical cycle. The metabolism of exogenous melatonin to the neurotransmitter serotonin may be regarded as a newly recognized additional component of its pharmacological action.

Footnotes

    • Received September 25, 2015.
    • Accepted January 7, 2016.
  • This research was supported by the European Union and the Polish Ministry of Science and Higher Education [Grant DeMeTer POIG.01.01.02-12-004/09] and by the Polish Academy of Sciences Institute of Pharmacology [Statutory Funds].

  • dx.doi.org/10.1124/dmd.115.067413.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleArticle

Melatonin Supports Serotonin Formation by Brain CYP2D

Anna Haduch, Ewa Bromek, Jacek Wójcikowski, Krystyna Gołembiowska and Władysława A. Daniel
Drug Metabolism and Disposition March 1, 2016, 44 (3) 445-452; DOI: https://doi.org/10.1124/dmd.115.067413

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Research ArticleArticle

Melatonin Supports Serotonin Formation by Brain CYP2D

Anna Haduch, Ewa Bromek, Jacek Wójcikowski, Krystyna Gołembiowska and Władysława A. Daniel
Drug Metabolism and Disposition March 1, 2016, 44 (3) 445-452; DOI: https://doi.org/10.1124/dmd.115.067413
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