Ondansetron, a highly selective 5-HT3 receptor antagonist, reduces L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.

L-3,4-dihydroxyphenylalanine (L-DOPA) has been the standard treatment for Parkinson's disease (PD), despite that its chronic use leads to motor fluctuations and dyskinesia in as many as 95% of patients. Previous studies have shown that serotonin type 3 (5-HT3) receptor blockade reduces dopamine levels within the striatum, suggesting that it could potentially lead to a reduction of dyskinesia. Here, we assessed the effects of ondansetron on L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat. We performed two series of experiments. First, rats exhibiting stable AIMs were administered ondansetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or vehicle in combination with L-DOPA, following which the effect of ondansetron on AIMs was assessed. In the second series of experiments, following 6-OHDA lesion, rats received daily administration of ondansetron (0.0001, 0.001 mg/kg) or vehicle, started concurrently with the first L-DOPA dose, and treatments were continued for 22 days. After a washout period, an acute L-DOPA challenge was administered and AIMs severity was assessed. The effect of ondansetron on L-DOPA anti-parkinsonian action was also determined. We found that the addition of ondansetron 0.0001 mg/kg to L-DOPA resulted in a significant reduction of AIMs severity (by 31%, P < 0.001), when compared to vehicle. Ondansetron 0.0001 mg/kg, when started concurrently with L-DOPA, also attenuated the development of AIMs, with AIMs being 64% less severe (P < 0.05), when compared to L-DOPA/vehicle. Ondansetron did not impair L-DOPA anti-parkinsonian action. Our results suggest that selective 5-HT3 blockade is a promising strategy to reduce the severity of L-DOPA-induced dyskinesia and may also attenuate its development.