Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice

ACS Chem Neurosci. 2013 Jan 16;4(1):84-8. doi: 10.1021/cn300127h. Epub 2012 Oct 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / genetics
  • Fluoxetine / adverse effects*
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Polymorphism, Genetic
  • Serotonin / deficiency*
  • Serotonin / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / drug effects
  • Serotonin Receptor Agonists / pharmacology
  • Serotonin Uptake Inhibitors / adverse effects*
  • Tryptophan Hydroxylase / genetics

Substances

  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Serotonin
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase