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Parkinson’s disease 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 functioning but often results in L-DOPA-induced dyskinesia (LID) typified by abnormal involuntary movements (AIMs). In this state of DA depletion, serotonin (5-HT) neuron hyperinnervation and glutamate overactivity are heavily implicated in LID. This study investigated the anti-dyskinetic effects of Vilazodone (VZD), a 5-HT transport blocker and partial 5-HT1a agonist, and/or Amantadine (AMAT), an NMDA glutamate antagonist. It was hypothesized that alone each would reduce LID, while co-administration at low doses would synergistically reduce LID without compromising L-DOPA efficacy. Hemiparkinsonian Sprague-Dawley rats were given L-DOPA (6mg/kg, s.c.) for 14 days to establish LID. VZD (0, 1, 2.5, 5mg/kg) and AMAT (0, 20, 40, 60mg/kg) were administered in a within-subjects counterbalanced design with L-DOPA to ascertain effective anti-LID doses (n=9). AIMs were monitored for 3 hours following injections to measure LID expression. Before examining potential treatment synergy, doses exhibiting minimal effect on AIMs scores were selected (VZD 1.0, 2.5mg/kg; AMAT 40mg/kg). The following cohort (n=8) received 6 counterbalanced treatments consisting of L-DOPA (6mg/kg) and either VZD (1, 2.5mg/kg), AMAT (40mg/kg), or both. Results revealed a significant decrease in AIMs and maintained motor performance with VZD (2.5mg/kg) compared to those receiving only L-DOPA. AMAT prolonged peak AIMs without maintaining L-DOPA motor efficacy when co-administered with VZD or L-DOPA alone. These results suggest co-administration of VZD and AMAT with L-DOPA does not synergistically reduce LID in hemiparkinsonian rats. Rather, our results suggest that AMAT may reduce the efficacy of VZD. However, our results suggest very low doses of VZD (2.5mg/kg) reduce LID severity and duration while maintaining L-DOPA efficacy.



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Investigating the Anti-dyskinetic Effects of Serotonin- and Glutamate-acting Compounds, Vilazodone and Amantadine, in Hemiparkinsonian Rats