Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal

Biol Psychiatry. 2008 Aug 15;64(4):293-301. doi: 10.1016/j.biopsych.2008.02.022. Epub 2008 Apr 11.


Background: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.

Methods: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling.

Results: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists.

Conclusions: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antidepressive Agents / classification
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Behavior, Animal / drug effects
  • Biogenic Monoamines / metabolism
  • Bromodeoxyuridine / metabolism
  • Cell Count / methods
  • Cell Proliferation / drug effects*
  • Cell Proliferation / radiation effects
  • Corticotropin-Releasing Hormone / metabolism
  • Depression / drug therapy
  • Depression / pathology*
  • Disease Models, Animal
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / radiation effects
  • Hemibody Irradiation / adverse effects
  • Hemibody Irradiation / methods
  • Hippocampus / pathology*
  • Hydrocarbons, Halogenated / pharmacology
  • Indoles / pharmacology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Motor Activity / drug effects
  • Neurons / drug effects*
  • Neurons / radiation effects
  • Pyrrolidines / pharmacology
  • Reaction Time / drug effects
  • Reaction Time / radiation effects
  • Thiazines / pharmacology
  • Time Factors


  • 1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide
  • Antidepressive Agents
  • Biogenic Monoamines
  • Hydrocarbons, Halogenated
  • Indoles
  • Pyrrolidines
  • SSR125543
  • Thiazines
  • Corticotropin-Releasing Hormone
  • Bromodeoxyuridine