Chronic L‐DOPA induces hyperactivity, normalization of gait and dyskinetic behavior in MitoPark mice

Dopamine (DA) replacement therapy continues to be the gold standard treatment for Parkinson's disease (PD), as it improves key motor symptoms including bradykinesia and gait disturbances. With time, treatment induces side effects in the majority of patients, known as L-DOPA-induced dyskinesia (LID), which are often studied in animals by the use of unilateral, toxin-induced rodent models. In this study, we used the progressive, genetic PD model MitoPark to specifically evaluate bilateral changes in motor behavior following long-term L-DOPA treatment at three different stages of striatal DA depletion. Besides locomotor activity, we assessed changes in gait with two automated gait analysis systems and the development of dyskinetic behavior. Long-term treatment with a moderate, clinically relevant dose of L-DOPA (8 mg/kg) gradually produced age-dependent hyperactivity in MitoPark mice. In voluntary and forced gait analyses, we show that MitoPark mice with severe DA depletion have distinct gait characteristics, which are normalized to control levels following long-term L-DOPA treatment. The cylinder test showed an age-dependent and gradual development of bilateral LID. Significant increase in striatal FosB and prodynorphin expression was found to accompany the behavior changes. Taken together, we report that MitoPark mice model both behavioral and biochemical characteristics of long-term L-DOPA treatment in PD patients and provide a novel, consistent and progressive animal model of dyskinesia to aid in the discovery and evaluation of better treatment options to counteract LID.