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The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease

1
Center for Neurodegenerative Disease & Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
2
School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
3
Stanson Toshok Center for Brain Function and Repair, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
4
Discipline of Neuroscience, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
5
Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(10), 2265; https://doi.org/10.3390/cells9102265
Received: 9 September 2020 / Revised: 5 October 2020 / Accepted: 6 October 2020 / Published: 9 October 2020
(This article belongs to the Collection Molecular and Cellular Mechanisms of Parkinson's Disease)
Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects. View Full-Text
Keywords: dopamine; serotonin; gene expression; L-DOPA; antidepressant; striatum; Parkinson’s disease dopamine; serotonin; gene expression; L-DOPA; antidepressant; striatum; Parkinson’s disease
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MDPI and ACS Style

Altwal, F.; Moon, C.; West, A.R.; Steiner, H. The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease. Cells 2020, 9, 2265. https://doi.org/10.3390/cells9102265

AMA Style

Altwal F, Moon C, West AR, Steiner H. The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease. Cells. 2020; 9(10):2265. https://doi.org/10.3390/cells9102265

Chicago/Turabian Style

Altwal, Feras, Connor Moon, Anthony R. West, and Heinz Steiner. 2020. "The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease" Cells 9, no. 10: 2265. https://doi.org/10.3390/cells9102265

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