Effects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain

RATIONALE: Vortioxetine is a novel multimodal antidepressant that is a 5-HT(1B) receptor partial agonist, a 5-HT(1A) receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT(1D), 5-HT(3), and 5-HT(7) receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT(1A) autoreceptors. OBJECTIVES: The aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT(1B) receptor and the tonic activation of 5-HT(1A) receptor in the rat hippocampus. METHODS: These receptors were assessed following vortioxetine administration acutely or subcutaneously using minipumps for 14 days. These studies were carried out using in vivo electrophysiological recording, microiontophoresis, and stimulation of the ascending 5-HT fibers. RESULTS: Vortioxetine enhanced the inhibitory effect of the stimulation of the 5-HT bundle at a high, but not low frequency and reversed the inhibitory effect of the 5-HT(1B) receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT(1B) receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT(1A) receptors on pyramidal neurons. Long-term administration of vortioxetine and escitalopram (both at 5 mg/kg/day) induced an increase of tonic activation of the 5-HT(1A) receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT(1B) autoreceptor following its sustained administration. CONCLUSIONS: Desensitization of 5-HT(1B) autoreceptor and an increase of tonic activation of 5-HT(1A) receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.