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Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans

The Pharmacogenomics Journal volume 13, pages 551–557 (2013)Cite this article

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Abstract

A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased ∼2.6–3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased ∼4.5–6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes.

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Acknowledgements

This research was supported by the NIMH Intramural Research Program and by NIH, NIMH RO1-MH39085 and the Boyd and Elsie Welin Professorship to JCS.

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Authors and Affiliations

  1. Laboratory of Clinical Science (LCS), National Institute of Mental Health, NIH, Bethesda, MD, USA

    M A Fox, M G Panessiti, P R Moya, T J Tolliver & D L Murphy

  2. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA

    K Chen & J C Shih

  3. Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    J C Shih

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  1. M A Fox
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Correspondence to M A Fox.

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Fox, M., Panessiti, M., Moya, P. et al. Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans. Pharmacogenomics J 13, 551–557 (2013). https://doi.org/10.1038/tpj.2012.35

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