Genetic regulation of behavioral and neuronal responses to fluoxetine

Neuropsychopharmacology. 2008 May;33(6):1312-22. doi: 10.1038/sj.npp.1301497. Epub 2007 Jul 4.

Abstract

Despite widespread use of antidepressants, the factors underlying the behavioral response to antidepressants are unknown. It has been shown that antidepressant treatment promotes the proliferation and survival of neurons in the adult hippocampus via enhanced serotonergic signaling, but it is unclear whether hippocampal neurogenesis is responsible for the behavioral response to antidepressants. Furthermore, a large subpopulation of patients fails to respond to antidepressant treatment due to presumed underlying genetic factors. In the present study, we have used the phenotypic and genotypic variability of inbred mouse strains to show that there is a genetic component to both the behavioral and neuronal effects of chronic fluoxetine treatment, and that this antidepressant induces an increase in hippocampal cell proliferation only in the strains that also show a positive behavioral response to treatment. Furthermore, the behavioral and neuronal responses are associated with an upregulation of genes known to promote neuronal proliferation and survival. These results suggest that inherent genetic predisposition to increased serotonin-induced neurogenesis may be a determinant of antidepressant efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects*
  • Bromodeoxyuridine / metabolism
  • Cell Differentiation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Fluoxetine / analogs & derivatives
  • Fluoxetine / blood
  • Fluoxetine / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Immobility Response, Tonic / drug effects
  • Male
  • Mice
  • Mice, Inbred Strains
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis / methods
  • Serotonin Uptake Inhibitors / blood
  • Serotonin Uptake Inhibitors / pharmacology*
  • Time Factors

Substances

  • Nerve Tissue Proteins
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Bromodeoxyuridine
  • norfluoxetine