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Parkinson's Disease (PD) is a debilitating, neurodegenerative disorder characterized by motor symptoms, including bradykinesia, tremor, stiffness, and postural instability, that result from significant nigrostriatal dopamine (DA) loss. The current gold standard treatment for PD involves replacement therapy via the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA); however, 90% of patients eventually experience choreic and dystonic side effects termed L-DOPA induced dyskinesia (LID). A key driver of LID is neuroplasticity within the serotonin (5-HT) system leading to the unregulated release of L-DOPA derived DA from 5-HT terminals into the striatum. Previous work has implicated the dual action of 5-HT1A receptor agonism and 5-HT transporter (SERT) blockade as an effective therapeutic method for attenuating LID. The present study examined 3 purportedly similar pharmacological drugs, Vilazodone, YL-0919, and Vortioxetine, that act as 5-HT1A agonists and SERT blockers. Adult female Sprague-Dawley rats received unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) to deplete DA neurons. Thereafter they received 2 weeks of L-DOPA treatment until they developed stable abnormal involuntary movement (AIMs) akin to LID. Rats were also assessed for motor performance with the forepaw adjusting steps (FAS) test. Results revealed that Vilazodone and Vortioxetine significantly reduced AIMs and maintained L-DOPA beneficial prokinetic effects. In contrast, YL-0919 unexpectedly had no effect on LID though it did maintain L-DOPA motor performance. Overall, these findings support pharmacological targets within the 5-HT system that reduce LID. They also provide evidence for unique features of Vilazodone and Vortioxetine, both FDA approved compounds, as potential adjunct therapeutics for LID management in PD patients.



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The Effects of Vilazodone, YL-0919, and Vortioxetine in L-DOPA Treated Hemiparkinsonian Rats