Chronic vortioxetine treatment improves the responsiveness to an acute stress acting through the ventral hippocampus in a glucocorticoid-dependent way

Vortioxetine is a novel multimodal antidepressant approved in 2013 by the Food and Drug Administration and the European Medicines Agency for the treatment of major depressive disorder (MDD). It combines the modulation of serotonin receptors activity with the inhibition of serotonin transporter (SERT). In this study, we aim at establishing the effect of chronic vortioxetine treatment (5 mg/kg twice/daily) in modulating neuroplastic mechanisms as well as hypothalamic pituitary adrenal axis (HPA) activity under basal condition and in response to an acute challenge. We found that prolonged vortioxetine administration significantly increased total Bdnf expression in the dorsal and ventral hippocampus of adult male rats and affected the stress-induced modulation of the immediate early genes Arc and Zif268, mainly in the ventral sub-region. Moreover, we also found that, within this brain area, chronic drug treatment was able to modulate glucocorticoid responsiveness at genomic level by enhancing the translocation of the glucocorticoid receptor (GR) in the nuclear compartment in response to the acute stress. Interestingly, this effect was mirrored by the up-regulation of different GR responsive-genes. Taken together, our data suggest that repeated exposure to vortioxetine specifically targets the ventral hippocampus by improving the ability to cope with stressful conditions. Moreover, its ability to facilitate HPA axis function might provide an indication to use this drug in patients characterized by glucocorticoid resistance.