Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor

Neuropsychopharmacology. 2008 Jan;33(2):406-17. doi: 10.1038/sj.npp.1301399. Epub 2007 Apr 11.


We previously reported that chronic, but not subchronic, treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine altered behavior in the forced swimming test (FST) in BALB/cJ mice. We now use this model to investigate mechanisms underlying the delayed onset of the behavioral response to antidepressants, specifically (1) adult hippocampal neurogenesis and (2) expression of the 5-HT1A receptor. Here, we show data validating this model of chronic antidepressant action. We found the FST to be selectively responsive to chronic administration of the SSRI fluoxetine (18 mg/kg/day) and the tricyclic antidepressant desipramine (20 mg/kg/day), but not to the antipsychotic haloperidol (1 mg/kg/day) in BALB/cJ mice. The behavioral effects of fluoxetine emerged by 12 days of treatment, and were affected neither by ablation of progenitor cells of the hippocampus nor by genetic deletion of the 5-HT1A receptor. The effect of fluoxetine in the BALB/cJ mice was also neurogenesis-independent in the novelty-induced hypophagia test. We also found that chronic fluoxetine does not induce an increase in cell proliferation or the number of young neurons as measured by BrdU and doublecortin immunolabeling, respectively, in BALB/cJ mice. These data are in contrast to our previous report using a different strain of mice (129SvEvTac). In conclusion, we find that BALB/cJ mice show a robust response to chronic SSRI treatment in the FST, which is not mediated by an increase in new neurons in the hippocampus, and does not require the 5-HT1A receptor. These findings suggest that SSRIs can produce antidepressant-like effects via distinct mechanisms in different mouse strains.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Exploratory Behavior / drug effects
  • Fluoxetine / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Hippocampus / radiation effects
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Motor Activity / drug effects
  • Neurons / drug effects
  • Neurons / physiology*
  • Neurons / radiation effects
  • Receptor, Serotonin, 5-HT1A / drug effects
  • Receptor, Serotonin, 5-HT1A / physiology*
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stress, Psychological
  • Swimming


  • Fluoxetine
  • Receptor, Serotonin, 5-HT1A