The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats

Authors

Sophie R. Cohen, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Michelle L. Terry, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Michael Coyle, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Emily Wheelis, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Ashley Centner, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Samantha Smith, Department of Psychology, Binghamton University, Binghamton, NY, USA.
John Glinski, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Natalie Lipari, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Carla Budrow, Department of Psychology, Binghamton University, Binghamton, NY, USA.
Fredric P. Manfredsson, Barrow Neurological Institute, Phoenix, AZ, USA.Follow
Christopher Bishop, Department of Psychology, Binghamton University, Binghamton, NY, USA. Electronic address: cbishop@binghamton.edu.

Document Type

Article

Abstract

Parkinson's disease (PD) is a progressive, neurodegenerative movement disorder caused by loss of nigrostriatal dopamine (DA) neurons. DA replacement therapy using L-3,4-dihydroxyphenylalanine (l-DOPA) improves motor function but often results in l-DOPA-induced dyskinesia (LID) typified by abnormal involuntary movements (AIMs). In states of DA depletion, striatal serotonin (5-HT) hyperinnervation and glutamate overactivity are implicated in LID. To target these co-mechanisms, this study investigated the potential anti-dyskinetic effects of FDA-approved Vilazodone (VZD), a 5-HT transport blocker and partial 5-HT agonist, and Amantadine (AMAT), a purported NMDA glutamate antagonist, in 6-hydroxydopamine-lesioned hemiparkinsonian Sprague-Dawley rats. Dose-response curves for each drug against l-DOPA-induced AIMs were determined to identify effective threshold doses. A second cohort of rats was tested using the threshold doses of VZD (1, 2.5 mg/kg, s.c.) and/or AMAT (40 mg/kg, s.c.) to examine their combined, acute effects on LID. In a third cohort, VZD and/or AMAT were administered daily with l-DOPA for 14 days to determine prophylactic effects on LID development. In a final cohort, rats with established LID received VZD and/or AMAT injections for 2 weeks to examine their interventional properties. Throughout experiments, AIMs were rated for dyskinesia severity and forepaw adjusting steps (FAS) were monitored l-DOPA motor efficacy. Results revealed that acute and chronic VZD + l-DOPA treatment significantly decreased AIMs and maintained FAS compared to l-DOPA alone. AMAT + l-DOPA co-administration did not exert any significant effects on AIMs or FAS, while the co-administration of VZD and AMAT with l-DOPA demonstrated intermediate effects. These results suggest that co-administration of low-dose VZD and AMAT with l-DOPA does not synergistically reduce LID in hemiparkinsonian rats. Importantly, low doses of VZD (2.5, 5 mg/kg) did reduce the development and expression of LID while maintaining l-DOPA efficacy, supporting its potential therapeutic utility for PD patients.

Keywords

6-OHDA, Amantadine, Parkinson's disease, Vilazodone, l-DOPA-induced dyskinesia

Medical Subject Headings

Amantadine (pharmacology, therapeutic use); Animals; Antiparkinson Agents (adverse effects); Disease Models, Animal; Dyskinesia, Drug-Induced (drug therapy, etiology); Excitatory Amino Acid Antagonists (therapeutic use); Humans; Levodopa (adverse effects); Oxidopamine; Parkinson Disease (drug therapy); Rats; Rats, Sprague-Dawley; Serotonin (metabolism); Vilazodone Hydrochloride (therapeutic use)

Publication Date

6-1-2022

Publication Title

Pharmacology, biochemistry, and behavior

E-ISSN

1873-5177

Volume

217

First Page

173393

PubMed ID

35513119

Digital Object Identifier (DOI)

10.1016/j.pbb.2022.173393

Recommended Citation

Cohen, Sophie R.; Terry, Michelle L.; Coyle, Michael; Wheelis, Emily; Centner, Ashley; Smith, Samantha; Glinski, John; Lipari, Natalie; Budrow, Carla; Manfredsson, Fredric P.; and Bishop, Christopher, "The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats" (2022). Translational Neuroscience. 2292.
https://scholar.barrowneuro.org/neurobiology/2292