Is striatal dopaminergic receptor imbalance responsible for levodopa-induced dyskinesia?

Summary— Abnormal involuntary movements (dyskinesias) of variable intensity eventually emerge in the majority of Parkinson's disease patients chronically treated with standard oral levodopa. They create social and physical embarrassment and narrow the therapeutic options normally proposed to improve Parkinsonian symptoms. Thus far, indirect clinical and experimental evidence has implicated the potential role of dopamine D₁ receptor activation in the generation of dopa dyskinesia. In recent years, our group has tested several dopaminergic agonists of variable half-life and selectivity in monkeys rendered Parkinsonian following toxic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These monkeys readily develop dyskinesia when treated with levodopa and provide the best animal model to study this complication. Our results in "drug-naive" and "dyskinesia-primed" MPTP animals suggest that pathological sensitisation of D₂ receptor-mediated striatal outflow is necessary and sufficient for the induction of dopa dyskinesia, with perhaps a synergistic contribution from D₁ receptors, and that repeated short-lived stimulation is important in the sensitisation process. This model supports the hypothesis that more continuous forms of dopaminomimetic therapy represent the best therapeutic approach for Parkinson's disease and calls for the development of novel D₁ agonists for further clinical testing.