Animal models of l-dopa-induced dyskinesia in Parkinson's disease.

Abstract

Understanding the biological mechanisms of l-dopa-induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing-off fluctuations and abnormal involuntary movements appearing when plasma levels of l-dopa are high, commonly referred to as peak-dose l-dopa-induced dyskinesia. Parkinsonian models exhibiting these features have been well-characterized in both rodent and nonhuman primate species. The first animal models of peak-dose l-dopa-induced dyskinesia were produced in monkeys lesioned with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated chronically with l-dopa to elicit choreic movements and dystonic postures. Seminal studies were performed in these models using both metabolic mapping and electrophysiological techniques, providing fundamental pathophysiological insights that have stood the test of time. A decade later, it was shown possible to reproduce peak-dose l-dopa-induced dyskinesia in rats and mice rendered parkinsonian with nigrostriatal 6-hydroxydopamine lesions. When treated with l-dopa, these animals exhibit abnormal involuntary movements having both hyperkinetic and dystonic components. These models have enabled molecular- and cellular-level investigations into the mechanisms of l-dopa-induced dyskinesia. A flourishing literature using genetically engineered mice is now unraveling the role of specific genes and neural circuits in the development of l-dopa-induced motor complications. Both non-human primate and rodent models of peak-dose l-dopa-induced dyskinesia have excellent construct validity and provide valuable tools for discovering therapeutic targets and evaluating potential treatments. © 2018 International Parkinson and Movement Disorder Society.