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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.

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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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          Author and article information

          Journal
          Pharmacogenomics J.
          The pharmacogenomics journal
          Springer Nature
          1473-1150
          1470-269X
          Dec 2013
          : 13
          : 6
          Affiliations
          [1 ] Laboratory of Clinical Science (LCS), National Institute of Mental Health, NIH, Bethesda, MD, USA.
          Article
          tpj201235 NIHMS415326
          10.1038/tpj.2012.35
          3562558
          22964922
          e4091695-a4d2-4814-88c1-28bffaba6c19
          History

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