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.

20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition

“…Pharmacogenetics studies on Maoa-deficient mice evidenced the counter indication of serotonergic drugs in these animals because of the risk of serotonergic syndrome complication. 45 MAOA agonists may be a good indication for reversing the behavioral symptoms (irritability, social withdrawal, stereotypy and repetitive speech) in the affected members, but such medication is not yet available. The role of atomoxetine, used in some countries for treatment of pervasive developmental disorders by targeting norepinephrine synaptic recapture, 46 could be questionable.…”

What Gene Mutations Affect Serotonin in Mice?

“…We examined the 9 specific cases that were associated with the GO term ‘dopamine metabolism’, to determine if both serotonin and dopamine levels changed in these mice and if those changes were in the same direction. Six of the mutations led to elevated serotonin and dopamine levels (Atp7a, Htr1a, Maoa, Maob, Park2, Park7), whereas in the other three mutations, dopamine was decreased while serotonin was increased (Nr4a2, Slc6a3, Snca) 5,6,7,8,9,10,11 . This is fairly consistent with the literature, where interactions between these neurotransmitters exist despite conflicting reports on the directionality of the changes.…”

Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice

“…In a separate cohort, EAAT3 HET and WT mice were killed by cervical dislocation. Brains were removed immediately and dissected on a glass-plate set in ice, weighed in an analytical balance and stored at −80 °C until use, as previously described [ 24 ]. Samples were homogenized according to a protocol modified from Cruz et al [ 25 ].…”