Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression

Neuron. 2009 May 28;62(4):479-93. doi: 10.1016/j.neuron.2009.04.017.

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, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Anxiety / chemically induced
  • Anxiety / diet therapy*
  • Anxiety / pathology
  • Arrestins / deficiency
  • Arrestins / genetics
  • Arrestins / metabolism
  • Bromodeoxyuridine / metabolism
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Corticosterone / toxicity
  • Depression / chemically induced
  • Depression / drug therapy*
  • Depression / pathology
  • Disease Models, Animal
  • Drug Administration Schedule
  • Exploratory Behavior / drug effects
  • Feeding Behavior / drug effects
  • Fluoxetine / therapeutic use*
  • GTP-Binding Protein alpha Subunit, Gi2 / genetics
  • GTP-Binding Protein alpha Subunit, Gi2 / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / radiation effects
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Hippocampus / radiation effects
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Hypothalamus / radiation effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Neurogenesis / drug effects*
  • Neurogenesis / radiation effects
  • Neuropeptides / metabolism
  • RNA, Messenger / metabolism
  • Radiation
  • Reaction Time / drug effects
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • Antidepressive Agents, Second-Generation
  • Arrb2 protein, mouse
  • Arrestins
  • Microtubule-Associated Proteins
  • Neuropeptides
  • RNA, Messenger
  • beta-Arrestin 2
  • beta-Arrestins
  • doublecortin protein
  • Fluoxetine
  • GTP-Binding Protein alpha Subunit, Gi2
  • Bromodeoxyuridine
  • Corticosterone