Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat

Biol Psychiatry. 2004 Oct 15;56(8):570-80. doi: 10.1016/j.biopsych.2004.07.008.


Background: There has been increasing evidence that atypical antipsychotics are effective in the treatment of mood disorders or for augmenting 5-hydroxytryptamine selective reuptake inhibitors for treatment-resistant depression.

Methods: Upregulation of neurogenesis in the adult hippocampus is a marker of antidepressant activity, and the present study investigated the influence of the atypical antipsychotic drug olanzapine on cell proliferation in the hippocampus of adult rat. The regulation of cell proliferation in the prelimbic cortex of adult rat was also examined.

Results: Chronic (21 days) olanzapine administration increased the number of newborn cells in the dentate gyrus of the hippocampus to the same extent as fluoxetine. Olanzapine or fluoxetine treatment also increased the number of proliferating cells in the prelimbic cortex. In contrast, there was no effect of either drug in the subventricular zone or primary motor cortex, and there was a trend for an increase in the striatum. Subchronic (7 days) administration of olanzapine had no effect on cell proliferation in hippocampus or prelimbic cortex, consistent with the time course for the effect of fluoxetine and the therapeutic actions of antidepressant treatment. The combination of olanzapine plus fluoxetine did not result in a greater induction of cell proliferation in either brain region. Analysis of the cell phenotype demonstrated that approximately 20% of the newborn cells in the prelimbic cortex differentiated into endothelial cells but not neurons, in contrast to the dentate gyrus, where most newborn cells differentiated into neurons.

Conclusions: The results demonstrate that antidepressant or atypical antipsychotic medications can increase the proliferation of glia in limbic brain structures, an effect that could reverse the loss of glia that has been observed in depressed patients.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antipsychotic Agents / administration & dosage*
  • Benzodiazepines / administration & dosage*
  • Bromodeoxyuridine / metabolism
  • Cell Count / methods
  • Cell Proliferation / drug effects*
  • Drug Administration Schedule
  • Drug Interactions
  • Endothelial Growth Factors / metabolism
  • Fluoxetine / administration & dosage*
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Immunohistochemistry / methods
  • Male
  • Nerve Growth Factors / metabolism
  • Nuclear Proteins / metabolism
  • O Antigens / metabolism
  • Olanzapine
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins / metabolism


  • Antipsychotic Agents
  • Endothelial Growth Factors
  • Nerve Growth Factors
  • Nuclear Proteins
  • O Antigens
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins
  • Fluoxetine
  • Benzodiazepines
  • Bromodeoxyuridine
  • Olanzapine