Mechanisms of NMDA receptor inhibition by vortioxetine – Comparison with fluoxetine

Abstract

N-methyl-D-aspartate receptors (NMDARs) are involved in the pathophysiology of depression and are inhibited by many antidepressants. In this work, we studied the action of the vortioxetine, a relatively new multitarget antidepressant, on native NMDARs in rat hippocampal CA1 pyramidal neurons and compared it to the action of structurally similar antidepressant fluoxetine. Vortioxetine inhibited these receptors with IC₅₀ value of 11 ± 1 μM at −80 mV holding voltage, being about three-fold more potent than fluoxetine in these conditions. The inhibition by both compounds was not competitive. Both vortioxetine and fluoxetine demonstrated complex voltage dependence with voltage-dependent and voltage-independent components. The voltage-dependent component corresponded to trapping channel block, while the voltage-independent component – to allosteric inhibition. Vortioxetine and fluoxetine were able to inhibit both open and closed NMDAR channels. Thus, NMDARs can be among important targets for vortioxetine or structurally related drugs. In addition, structural similarity of vortioxetine and fluoxetine allows to assume that these compounds may share other molecular targets besides serotonin transporter and NMDARs.