Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress

The antidepressant agomelatine is a MT(1)/MT(2) receptor agonist and 5-HT(2C) antagonist. Its antidepressant activity is proposed to result from the synergy between these sets of receptors. Agomelatine-induced changes in the brain have been reported under basal conditions. Yet, little is known about its effects in the brain exposed to chronic stress as a risk factor for major depressive disorder. Recently, we described agomelatine-induced changes on neuronal activity and adult neurogenesis in the hippocampus of rats subjected to chronic footshock stress. In order to better characterize the actions of agomelatine in the stress-compromised brain, here we investigated its effects on hippocampal neurogenesis in the chronic mild stress (CMS) model. Adult male rats were subjected to various mild stressors for 5 weeks, and treated with agomelatine during the last 3 weeks of the stress period. The sucrose preference test was performed weekly to measure anhedonia, and the marble burying test was carried out at the end of the experiment to assess anxiety-like behavior. In our model, the CMS paradigm did not change sucrose preference; however, it increased marble burying behavior, indicating enhanced anxiety. Interestingly, this stress model differentially affected distinct stages of the neurogenesis process. Whereas CMS did not influence the rate of hippocampal cell proliferation, it significantly decreased the newborn cell survival and doublecortin expression in the dentate gyrus. Importantly, treatment with agomelatine completely normalized stress-affected cell survival and partly reversed reduced doublecortin expression. Taken together, these data show that agomelatine has beneficial effects on hippocampal neurogenesis in the CMS paradigm.