title: Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice.
abstract: Selective 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.
authors: Department of Cell Biology, Duke University, Durham, North Carolina 27710, United States.
authors: William B
authors: WB
authors: Siesser
authors: Benjamin D
authors: BD
authors: Sachs
authors: Amy J
authors: AJ
authors: Ramsey
authors: Tatyana D
authors: TD
authors: Sotnikova
authors: Jean-Martin
authors: JM
authors: Beaulieu
authors: Xiaodong
authors: X
authors: Zhang
authors: Marc G
authors: MG
authors: Caron
authors: Raul R
authors: RR
authors: Gainetdinov
mesh_terms: D000818:Animals; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D005473:Fluoxetine / Q000009:adverse effects*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D011110:Polymorphism, Genetic; D012701:Serotonin / Q000172:deficiency* / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*; D014365:Tryptophan Hydroxylase / Q000235:genetics
chemical_list: D005473:Fluoxetine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase; C487802:Tph2 protein, mouse