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Download fileChronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice
journal contribution
posted on 2016-02-20, 01:25 authored by William
B. Siesser, Benjamin D. Sachs, Amy J. Ramsey, Tatyana D. Sotnikova, Jean-Martin Beaulieu, Xiaodong Zhang, Marc G. Caron, Raul R. GainetdinovSelective serotonin reuptake inhibitors (SSRIs) are a
major class
of antidepressants that act by blocking inward transport of serotonin
(5-HT) into presynaptic neurons mediated by the serotonin transporter
(SERT). Both reuptake and ongoing synthesis are essential in supporting
intraneuronal serotonin concentrations in serotonergic neurons. A
rare mutation in tryptophan hydroxylase 2 (Tph2),
the rate limiting enzyme for 5-HT synthesis, was identified in several
patients with major depression, and knock-in mice expressing the analogous
mutation (R439H Tph2 KI) show 80% reduction in 5-HT
synthesis and tissue levels. Chronic treatment with SSRIs (fluoxetine
and paroxetine) resulted in a dramatic further depletion of 5-HT tissue
levels in R439H Tph2 KI mice (down to 1–3%
of wild type levels) while having little effects in wild-type controls.
Treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) restored
5-HT tissue content in mutant mice, and cotreatment with 5-HTP and
fluoxetine essentially prevented the depleting effect of a chronic
SSRI. These data demonstrate that chronic SSRI treatment could further
exacerbate the 5-HT deficiency in Tph2 mutation carriers,
and this can be prevented by 5-HTP supplementation.
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Tph 2 mutation carriersR 439H Tph 2 KI miceserotonergic neuronstype levelspresynaptic neuronsChronic treatmentHTSERTChronic SSRI Treatment Exacerbates Serotonin DeficiencyR 439H Tph 2 KIserotonin transporterintraneuronal serotonin concentrationsHTPdepleting effecttissue levelssynthesistryptophan hydroxylase 2Humanized Tph 2 Mutant MiceSelective serotonin reuptake inhibitorsSSRI treatment