Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/Depression

Denis J. David, Benjamin Adam Samuels, Quentin Rainer, Jing Wen Wang, Douglas Marsteller, Indira Mendez, Michael Drew, Douglas A. Craig, Bruno P. Guiard, Jean Philippe Guilloux, Roman P. Artymyshyn, Alain M. Gardier, Christophe Gerald, Irina A. Antonijevic, E. David Leonardo, René Hen

Research output: Contribution to journalArticlepeer-review

795 Scopus citations

Abstract

Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, β-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that β-arrestin signaling is necessary for the antidepressant effects of fluoxetine.

Original languageEnglish (US)
Pages (from-to)479-493
Number of pages15
JournalNeuron
Volume62
Issue number4
DOIs
StatePublished - May 28 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • HUMDISEASE
  • MOLNEURO
  • STEMCELL

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