Stimulation of neurogenesis in the hippocampus of the adult rat by fluoxetine requires rhythmic change in corticosterone

Background: Fluoxetine stimulates proliferation of progenitor cells in the dentate gyrus of the adult hippocampus. There are suggestions that this action may underlie the therapeutic effects of such drugs in depression. Glucocorticoids also regulate neurogenesis, and there are multiple interactions between serotonin and corticoids. Diurnal cortisol rhythms are dysregulated in depression. We explored the role of diurnal variations in corticosterone on the ability of fluoxetine to alter neurogenesis in the dentate gyrus. Methods: We manipulated plasma corticosterone by implanting corticosterone pellets or giving daily corticosterone injection to corticosterone-clamped adrenalectomized or intact rats that received fluoxetine or vehicle treatment. Proliferation of progenitor cells in the dentate gyrus was measured using BrdU or Ki-67. Results: Our results strongly suggest that a diurnal rhythm in corticosterone is necessary for fluoxetine to stimulate neurogenesis in the adult dentate gyrus in the male rat. Preliminary data suggest this may be related to the 5-HT1A receptor. Conclusions: If altered neurogenesis in the dentate gyrus is part of the therapeutic response to antidepressants such as fluoxetine, the results we report suggest that concurrent manipulation of the HPA axis might improve sensitivity to selective serotonin reuptake inhibitors in some treatment-resistant patients.