Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory

Depression is frequently associated with cognitive disturbances. Vortioxetine is a multimodal acting antidepressant that functions as a 5-HT₃ and 5-HT₇ and 5-HT_1D receptor antagonist, 5-HT_1B receptor partial agonist, 5-HT_1A receptor agonist and inhibitor of the 5-HT transporter. Given its pharmacological profile, the present study was undertaken to determine whether vortioxetine could modulate several preclinical parameters known to be involved in cognitive processing.In the dorsal hippocampus of anaesthetized rats, the high-frequency stimulation of the Schaffer collaterals provoked a stable long-term potentiation (LTP) of ~25%. Interestingly, vortioxetine (10mg/kg, i.p.) counteracted the suppressant effect of elevated platform stress on hippocampal LTP induction. In the novel object recognition test, vortioxetine (10mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this pro-cognitive effect was prevented by the partial 5-HT₃ receptor agonist SR57227 (1mg/kg, i.p.). Finally, compared to fluoxetine, sustained administration of vortioxetine (5mg/kg/day, s.c.) induced a rapid increase of cell proliferation in the hippocampal dentate gyrus.In summary, vortioxetine prevented the effect of stress on hippocampal LTP, increased rapidly hippocampal cell proliferation and enhanced short-term episodic memory, via, at least in part, its 5-HT₃ receptor antagonism. Taken together, these preclinical data suggest that the antidepressant vortioxetine may have a beneficial effect on human cognitive processes.