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Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/Bl6 mice

Molecular Psychiatry volume 13, pages 498–506 (2008)Cite this article

Abstract

Considerable attention has focused on regulation of central tryptophan hydroxylase (TPH) activity and protein expression. At the time of these earlier studies, it was thought that there was a single central TPH isoform. However, with the recent identification of TPH2, it becomes important to distinguish between regulatory effects on the protein expression and activity of the two isoforms. We have generated a TPH2-specific polyclonal antiserum (TPH2-6361) to study regulation of TPH2 at the protein level and to examine the distribution of TPH2 expression in rodent and human brain. TPH2 immunoreactivity (IR) was detected throughout the raphe nuclei, in lateral hypothalamic nuclei and in the pineal body of rodent and human brain. In addition, a prominent TPH2-IR fiber network was found in the human median eminence. We recently reported that glucocorticoid treatment of C57/Bl6 mice for 4 days markedly decreased TPH2 messenger RNA levels in the raphe nuclei, whereas TPH1 mRNA was unaffected. The glucocorticoid-elicited inhibition of TPH2 gene expression was blocked by co-administration of the glucocorticoid receptor antagonist mifepristone (RU-486). Using TPH2-6361, we have extended these findings to show a dose-dependent decrease in raphe TPH2 protein levels in response to 4 days of treatment with dexamethasone; this effect was blocked by co-administration of mifepristone. Moreover, the glucocorticoid-elicited inhibition of TPH2 was functionally significant: serotonin synthesis was significantly reduced in the frontal cortex of glucocorticoid-treated mice, an effect that was blocked by mifepristone co-administration. This study provides further evidence for the glucocorticoid regulation of serotonin biosynthesis via inhibition of TPH2 expression, and suggest that elevated glucocorticoid levels may be relevant to the etiology of psychiatric diseases, such as depression, where hypothalamic-pituitary-adrenal axis dysregulation has been documented.

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Acknowledgements

We thank S Adamski for her technical expertise, S Alves and S Rohrer for their support, and M Palkovits for generous provision of the human tissue samples. S Key, I Szalayova and E Mezey are supported by the NIH intramural program, NIDCR.

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Author notes

  1. R K Conley

    Present address: 7Current address: Discovery Biology, Pfizer Global Research and Development, Kent CT13 9NJ, UK.,

Authors and Affiliations

  1. Stroke and Neurodegeneration, Merck Research Laboratories, West Point, PA, USA

    J A Clark & R B Flick

  2. Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ, USA

    L-Y Pai

  3. Craniofacial & Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD, USA

    I Szalayova, S Key & E Mezey

  4. Sleep and Schizophrenia, Merck Research Laboratories, West Point, PA, USA

    R K Conley & P H Hutson

  5. Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA

    A Y Deutch

  6. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    A Y Deutch

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Correspondence to J A Clark.

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Clark, J., Flick, R., Pai, LY. et al. Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/Bl6 mice. Mol Psychiatry 13, 498–506 (2008). https://doi.org/10.1038/sj.mp.4002041

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