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

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-HT1A 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 + LDOPA 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.

Automated summary

This study investigated the effects of the combination of Vilazodone (VZD), a 5-HT transport blocker, and Amantadine (AMAT), an NMDA glutamate antagonist, on Parkinson's disease (PD) motor disorders. The results showed that low doses of VZD and AMAT combined with L-DOPA can reduce dyskinesia and maintain treatment efficacy.