Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat.
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.
Division of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Masafumi
M
Kodama
Takashi
T
Fujioka
Ronald S
RS
Duman
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016228:Endothelial Growth Factors / Q000378:metabolism; D005473:Fluoxetine / Q000008:administration & dosage*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D019081:O Antigens / Q000378:metabolism; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism
D014150:Antipsychotic Agents; D016228:Endothelial Growth Factors; D009414:Nerve Growth Factors; D009687:Nuclear Proteins; D019081:O Antigens; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D005473:Fluoxetine; D001569:Benzodiazepines; D001973:Bromodeoxyuridine; D000077152:Olanzapine