Objective: To determine the effect of the serotonin 3 (5-HT3) receptor antagonist granisetron, a clinically-available anti-emetic, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia.

Background: Dopamine replacement with L-DOPA is the most effective symptomatic treatment for Parkinson’s disease (PD), however, long-term therapy leads to dyskinesia. 5-HT3 receptor blockade reduces dopamine levels in the striatum, which suggests that 5-HT3 receptor antagonists could mitigate the aberrant release of dopamine that occurs in dyskinesia, thereby diminishing the severity of dyskinesia in PD. In the present study, we hypothesised that granisetron would alleviate dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat.

Methods: Following 6-OHDA lesion of the right medial forebrain bundle, rats underwent the cylinder test to assess the degree of parkinsonism. Severely parkinsonian rats were selected for priming with L-DOPA to exhibit stable and reproducible abnormal involuntary movements (AIMs). On experimental days, granisetron (0.0001, 0.001, 0.01, 0.1 or 1 mg/kg) or vehicle was administered in combination with L-DOPA, and duration and amplitude of axial, limbs and oro-lingual (ALO) AIMs severity were evaluated. Following a 2-day washout period, preference for the un-lesioned forelimb was measured by the cylinder test to assess the effect of granisetron on L-DOPA anti-parkinsonian action.

Results: In combination with L-DOPA, granisetron 0.01 mg/kg significantly diminished both duration and amplitude of ALO AIMs by 46% and 50%, respectively (P < 0.05 and P < 0.01), compared to vehicle. Moreover, the anti-dyskinetic effect of granisetron was achieved without hindering L-DOPA anti-parkinsonian action.

Conclusions: Our results suggest that granisetron is a potential drug candidate to effectively alleviate L-DOPA-induced dyskinesia without impairing the therapeutic efficacy of L-DOPA. Because it is already available in the clinic, our results could quickly lead to clinical trials. Moreover, coupled with the companion Abstract on ondansetron, our results suggest that selective 5-HT3 receptor blockade is a potentially effective anti-dyskinetic approach likely to be well tolerated by PD patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-anti-dyskinetic-effect-of-the-clinically-available-5-ht3-receptor-antagonist-granisetron-in-the-6-ohda-lesioned-rat-model-of-parkinsons-disease/