Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Siesser, WB; Sachs, BD; Ramsey, AJ; Sotnikova, TD; Beaulieu, J-M; Zhang, X; Caron, MG; Gainetdinov, RR

Published Date

  • January 16, 2013

Published In

Volume / Issue

  • 4 / 1

Start / End Page

  • 84 - 88

PubMed ID

  • 23336047

Pubmed Central ID

  • 23336047

Electronic International Standard Serial Number (EISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/cn300127h

Language

  • eng

Conference Location

  • United States