Fluoxetine attenuates stress-induced depressive-like behavior through modulation of hippocampal GAP43 and neurogenesis in male rats

Based on the monoaminergic theory, Serotonin-Selective Reuptake Inhibitors (SSRIs) are used for treating depression. Recent hypotheses suggest that antidepressants may influence neurogenesis and synaptic plasticity. However, the mechanisms underlying these effects are still poorly understood. The aim of the present study was to evaluate the effect of fluoxetine, a widely used SSRI antidepressant, on the neurogenesis and the expression of Growth-Associated Protein 43 (GAP43), a synaptic protein, in the rat hippocampus exposed to Unpredictable Chronic Mild Stress (UCMS; the model of depressive-like behavior). We have analyzed the effects of chronic fluoxetine treatment on immobility behavior (forced swimming test), plasma interleukin-6 and corticosterone (enzyme-linked immunosorbent assay), BrdU-positive cells in the dentate gyms and GAP43 expression in the CA3 region (Immunohistochemistry) of the hippocampus. This study provides evidence that fluoxetine is a potent enhancer of GAP-43, a protein related to the neuronal plasticity, in the hippocampus of the rat model of depression. Interestingly, our results showed that although fluoxetine significantly is effective in increasing BrdU positive cells, it is more effective in increasing the neurite formation compared with neurogenesis. The results support the idea that antidepressants can promote neuronal plasticity. We concluded that the increase of GAP-43- induced neurite formation may be an important mechanism by which fluoxetine augments hippocampal neuroplasticity and play its pivotal antidepressant role.