Broad Serotonergic Actions of Vortioxetine as a Promising Avenue for the Treatment of L-DOPA-Induced Dyskinesia

Abstract

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor symptoms that result from loss of nigrostriatal dopamine (DA) cells. While L-DOPA provides symptom alleviation, its chronic use often results in the development of L-DOPA-induced dyskinesia (LID). Evidence suggests that neuroplasticity within the serotonin (5-HT) system contributes to LID onset, persistence, and severity. This has been supported by research showing 5-HT compounds targeting 5-HT1A/1B receptors and/or the 5-HT transporter (SERT) can reduce LID. Recently, vortioxetine, a multimodal 5-HT compound developed for depression, demonstrated acute anti-dyskinetic effects. However, the durability and underlying pharmacology of vortioxetine’s anti-dyskinetic actions have yet to be delineated. To address these gaps, we used hemiparkinsonian rats in Experiment 1, examining the effects of sub-chronic vortioxetine on established LID and motor performance. In Experiment 2, we applied the 5-HT1A antagonist WAY-100635 or 5-HT1B antagonist SB-224289 in conjunction with L-DOPA and vortioxetine to determine the contributions of each receptor to vortioxetine’s effects. The results revealed that vortioxetine consistently and dose-dependently attenuated LID while independently, 5-HT1A and 5-HT1B receptors each partially reversed vortioxetine’s effects. Such findings further support the promise of pharmacological strategies, such as vortioxetine, and indicate that broad 5-HT actions may provide durable responses without significant side effects.

Atractylenolide I improves behaviors in mice with depression‐like phenotype by modulating neurotransmitter balance via 5‐HT2A

“…Since the negative feedback inhibition resulting from the activation of 5‐HT1A autoreceptors plays a key role in the delay of antidepressant onset, it is possible to relieve the negative feedback inhibition caused by the activation of presynaptic 5‐HT receptors if antidepressants with both 5‐HT re‐uptake inhibitory and presynaptic 5‐HT receptor antagonistic functions can be developed, achieving the goal of fast efficacy (Fleischman et al, 2023; Zhou et al, 2023). Research has shown that a combination of 5‐HT receptor antagonist WAY‐100635 and selective serotonin reuptake inhibitor (SSRIs) can relieve SSRIs' inhibitory effect against the 5‐HT neuronal firing, and significantly enhance the SSRIs‐induced elevation of 5‐HT level in synaptic clefts (Budrow et al, 2023). Given the current lack of selective 5‐HT1A autoreceptor antagonists, the non‐selective 5‐HT antagonists may block both the pre‐ and postsynaptic 5‐HT1A receptors to cancel the antidepressant effect.…”