title: Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans.
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.
authors.affiliation: Laboratory of Clinical Science (LCS), National Institute of Mental Health, NIH, Bethesda, MD, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Fox
authors.forename: M G
authors.initials: MG
authors.lastname: Panessiti
authors.forename: P R
authors.initials: PR
authors.lastname: Moya
authors.forename: T J
authors.initials: TJ
authors.lastname: Tolliver
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.forename: J C
authors.initials: JC
authors.lastname: Shih
authors.forename: D L
authors.initials: DL
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004342:Drug Hypersensitivity; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000235:genetics*; D009154:Mutation; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D008995:Monoamine Oxidase; D017367:Selective Serotonin Reuptake Inhibitors