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

Carla Budrow, Kayla Elder, Michael Coyle, Ashley Centner, Natalie Lipari, Sophie Cohen, John Glinski, N'Senga Kinzonzi, Emily Wheelis, Grace McManus, Fredric Manfredsson, Christopher Bishop

Cells 2023 Mar 08

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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.

Citation

Carla Budrow, Kayla Elder, Michael Coyle, Ashley Centner, Natalie Lipari, Sophie Cohen, John Glinski, N'Senga Kinzonzi, Emily Wheelis, Grace McManus, Fredric Manfredsson, Christopher Bishop. Broad Serotonergic Actions of Vortioxetine as a Promising Avenue for the Treatment of L-DOPA-Induced Dyskinesia. Cells. 2023 Mar 08;12(6)