Selective blockade of the 5-HT receptor acutely alleviates dyskinesia and psychosis in the parkinsonian marmoset.

Neuropharmacology

Neurodegenerative Disease Group, Montreal Neurological Institute, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Movement Disorder Clinic, Division of Neurology, Department of Neuroscience, McGill University Health Centre, Montreal, QC, Canada. Electronic address:

Published: January 2021

AI Article Synopsis

  • Parkinson's disease patients suffer from complications related to l-DOPA treatment, such as dyskinesia and psychosis, which negatively impact their quality of life.
  • In a study using a non-human primate model, ondansetron significantly reduced the severity of dyskinesia and psychosis-like behaviors when administered alongside chronic l-DOPA.
  • The results indicate that ondansetron, a 5-HT receptor antagonist, may be an effective way to manage l-DOPA-related complications and enhance the benefits of l-DOPA treatment.

Article Abstract

In Parkinson's disease (PD), management of L-3,4-dihydroxyphenylalanine (l-DOPA)-related complications, such as l-DOPA induced dyskinesia and psychosis, remains inadequate, which poses a significant burden on the quality of life of patients. We have shown, in the hemi-parkinsonian rat model of PD, that the selective serotonin type 3 (5-HT) receptor antagonists ondansetron and granisetron decreased the severity of established dyskinesia, and ondansetron even attenuated the development of dyskinesia. Here, we seek to confirm these favourable data on dyskinesia and to explore the effect of ondansetron on the severity of psychosis-like behaviours (PLBs) in the gold standard model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate. We first determined the pharmacokinetic profile of ondansetron in the marmoset. Subsequently, six MPTP-lesioned marmosets were administered l-DOPA chronically until they exhibited stable and reproducible dyskinesia and PLBs upon each administration of l-DOPA. On behavioural assessment days, ondansetron (0.01, 0.1 and 1 mg/kg) or vehicle was administered in conjunction with l-DOPA, and the severity of dyskinesia, PLBs and parkinsonism was evaluated. Ondansetron 0.1 mg/kg alleviated global dyskinesia severity by 73% (P < 0.0001) and decreased duration of on-time with disabling dyskinesia by 88% (P = 0.0491). Ondansetron 0.1 mg/kg reduced the severity of global PLBs by 80% (P < 0.0001) and suppressed on-time with disabling PLBs (P = 0.0213). Ondansetron enhanced the anti-parkinsonian action of l-DOPA, reducing global parkinsonism by 53% compared to l-DOPA (P = 0.0004). These results suggest that selective blockade of the 5-HT receptor with ondansetron may be an effective approach to alleviate l-DOPA-related complications.

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http://dx.doi.org/10.1016/j.neuropharm.2020.108386DOI Listing

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