Objective: To determine the effectiveness of selective serotonin 3 (5-HT3) receptor blockade at reducing the severity of established, and preventing the development of, dyskinesia.

Background: L-3,4-dihydroxyphenylalanine (L-DOPA) therapy is the most effective treatment for Parkinson’s disease, but with chronic L-DOPA administration, complications such as dyskinesia emerge. It has been shown 5-HT3 blockade reduces dopamine levels within the basal ganglia, suggesting that it could potentially lead to a reduction of dyskinesia. Here, we hypothesised that 5HT3 blockade would effectively alleviate L-DOPA-induced dyskinesia.

Methods: Rats were rendered hemi-parkinsonian by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. The degree of parkinsonism was assessed by the cylinder test. Two sets of experiments were then conducted. In the first set of experiments, rats were primed with L-DOPA to elicit stable and reproducible axial, limbs and oro-lingual (ALO) abnormal involuntary movements (AIMs), after which they were administered acute challenges of ondansetron (0.0001, 0.001, 0.01, 0.1 or 1 mg/kg) or vehicle in combination with L-DOPA and the severity of ALO AIMs was rated. In the second set of experiments, following 6-OHDA lesion, rats were administered ondansetron 0.0001 mg/kg or vehicle, started concurrently with L-DOPA, once daily for 22 days, during which the severity of ALO AIMs was assessed regularly. After a 2-day washout period, an acute L-DOPA challenge was administered and ALO AIMs severity was assessed. The effect of ondansetron on L-DOPA anti-parkinsonian action was also determined by the cylinder test.

Results: The addition of ondansetron 0.0001 mg/kg to L-DOPA resulted in a significant decrease of ALO AIMs duration and amplitude, by 53% and 51%, respectively (both P < 0.01), when compared to vehicle. Ondansetron, when started concurrently with L-DOPA, also attenuated ALO AIMs by 51% (P < 0.05), when compared to vehicle. The anti-dyskinetic effect of ondansetron was achieved without impairing L-DOPA anti-parkinsonian action.

Conclusions: Our results suggest that the potent, highly-selective and clinically-available 5-HT3 antagonist ondansetron is a promising molecule to reduce the severity, and attenuate the development, of L-DOPA-induced dyskinesia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ondansetron-a-highly-selective-5-ht3-receptor-antagonist-alleviates-l-dopa-induced-dyskinesia-in-the-6-ohda-lesioned-rat-model-of-parkinsons-disease/