The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine.

Published

Journal Article

The importance of reversing brain serotonin (5-HT) deficiency and promoting hippocampal neurogenesis in the mechanisms of action for antidepressants remain highly controversial. Here we examined the behavioral, neurochemical and neurogenic effects of chronic fluoxetine (FLX) in a mouse model of congenital 5-HT deficiency, the tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mouse. Our results demonstrate that congenital 5-HT deficiency prevents a subset of the signature molecular, cellular and behavioral effects of FLX, despite the fact that FLX restores the 5-HT levels of Tph2KI mice to essentially the levels observed in wild-type mice at baseline. These results suggest that inducing supra-physiological levels of 5-HT, not merely reversing 5-HT deficiency, is required for many of the antidepressant-like effects of FLX. We also demonstrate that co-administration of the 5-HT precursor, 5-hydroxytryptophan (5-HTP), along with FLX rescues the novelty suppressed feeding (NSF) anxiolytic-like effect of FLX in Tph2KI mice, despite still failing to induce neurogenesis. Thus, our results indicate that brain 5-HT deficiency reduces the efficacy of FLX and that supplementation with 5-HTP can restore some antidepressant-like responses in the context of 5-HT deficiency. Our findings also suggest that feeding latency reductions in the NSF induced by chronic 5-HT elevation are not mediated by drug-induced increments in neurogenesis in 5-HT-deficient animals. Overall, these findings shed new light on the impact of 5-HT deficiency on responses to FLX and may have important implications for treatment selection in depression and anxiety disorders.

Full Text

Duke Authors

Cited Authors

  • Sachs, BD; Jacobsen, JPR; Thomas, TL; Siesser, WB; Roberts, WL; Caron, MG

Published Date

  • August 13, 2013

Published In

Volume / Issue

  • 3 /

Start / End Page

  • e291 -

PubMed ID

  • 23942622

Pubmed Central ID

  • 23942622

Electronic International Standard Serial Number (EISSN)

  • 2158-3188

International Standard Serial Number (ISSN)

  • 2158-3188

Digital Object Identifier (DOI)

  • 10.1038/tp.2013.65

Language

  • eng