Lithium, but Not Fluoxetine or the Corticotropin-Releasing Factor Receptor 1 Receptor Antagonist R121919, Increases Cell Proliferation in the Adult Dentate Gyrus

Several antidepressant drugs have previously been reported to increase neurogenesis in the dentate gyrus of the hippocampus in laboratory animals. We found no effect of the selective serotonin reuptake inhibitor fluoxetine or the corticotropin-releasing factor receptor 1 antagonist R121919 [3-[6-(dimethylamino)-4-methylpyridin-3-yl]-2,5-dimethyl-N,N-dipropyl-1H-pyrazolo[1,5-a]pyrimidin-8-ium-7-amine] on the rate of cell proliferation or hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression in either adult or adolescent rats after long-term administration. In adults, the mood stabilizer lithium was found to significantly increase cell proliferation; the atypical antipsychotic paliperidone did not affect proliferation, either alone or when combined with lithium. Fourteen-day survival of neuronally fated cells showed a significant interaction effect of lithium and paliperidone but no effect of either drug alone. BDNF mRNA expression was significantly decreased by lithium in the CA1/2 cell fields and increased by paliperidone in the CA1/2, CA3, and dentate gyrus. These results raise questions concerning the hypothesis that all antidepressants increase neurogenesis under nonstressed conditions. They also confirm and extend previous reports of lithium-induced increases in cell proliferation but not survival.