Abstract
RationaleVortioxetine is a novel multimodal antidepressant that is a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT1A autoreceptors.ObjectivesThe aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT1B receptor and the tonic activation of 5-HT1A receptor in the rat hippocampus.MethodsThese 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.ResultsVortioxetine 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-HT1B receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT1B receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT1A 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-HT1A receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT1B autoreceptor following its sustained administration.ConclusionsDesensitization of 5-HT1B autoreceptor and an increase of tonic activation of 5-HT1A receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.
Highlights
Clinical studies have established that vortioxetine is an effective antidepressant with a potential benefit on cognitive functions (Citrome 2014; McIntyre et al 2013; Alvarez et al 2014; Katona et al 2012; Mahableshwarkar et al 2014)
In order to examine the net effect of vortioxetine on terminal 5HT1B autoreceptor activation by electrically evoked release of endogenous 5-HT, the effectiveness of two series of stimulations was delivered at different frequencies while recording from same pyramidal neuron
The present study showed that vortioxetine acted as a 5-HT1B receptor partial agonist because it competed with both an exogenous 5-HT1B receptor agonist and endogenous 5-HT under high but not low degree of activation of the terminal 5-HT1B autoreceptor
Summary
Clinical studies have established that vortioxetine is an effective antidepressant with a potential benefit on cognitive functions (Citrome 2014; McIntyre et al 2013; Alvarez et al 2014; Katona et al 2012; Mahableshwarkar et al 2014). Vortioxetine displays two modes of pharmacological action on the serotonin (5-hydroxytryptamine, 5-HT) system: it selectively blocks the 5-HT transporter (5-HTT) and binds with moderate to high affinity to human (h) 5-HT1A, 5HT1B, 5-HT1D, 5-HT3, and 5-HT7 receptors (Mørk et al 2012). A previous electrophysiological study showed that acute administration of vortioxetine potently suppresses the firing rate of dorsal raphe (DR) 5-HT neurons without optimally occupying the 5-HTT (Bétry et al 2013) This is unlikely to result from a direct activation of the somatodendritic 5-HT1A autoreceptors because vortioxetine has an affinity about 30 times lower for the rat (r)5-HT1A receptor than for the 5HTT (Mørk et al 2012; Pehrson et al 2013). This marked suppression of firing may be due to the enhanced synaptic 5-HT availability resulting from synergy between 5HTT inhibition and activation of receptor(s), as it is reversed
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