The effects of chronic L-DOPA therapy on pharmacodynamic parameters in a rat model of motor response fluctuations

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy in Parkinson's disease (PD) is complicated by motor response fluctuations and dyskinesia. The relative contributions of disease severity and chronic L-DOPA therapy to the development of motor fluctuation are not well defined clinically. Experimental studies have been limited partly because models for the antiparkinsonian effects on akinesia have not been employed. Therefore, we employed a model of akinesia using forepaw adjusting steps that have been well characterized to reflect the effect of lesions and the antiparkinsonian effect of dopaminergic drugs and transplants. We administered L-DOPA (12.5 mg/kg) intermittently for 4 weeks to rats with severe nigrostriatal lesions produced by injecting 6-hydroxydopamine into the medial forebrain bundle. The peak magnitude responses to L-DOPA increased after treatment compared to the pretreatment baseline. The latency to peak response to L-DOPA became shorter and reversed after the discontinuation of treatment. The duration of response showed minor changes. The pattern of changes in response to apomorphine was similar to that of L-DOPA except that the peak magnitude did not increase despite chronic L-DOPA treatment. The changes in D1 and D2 receptor binding did not correlate with behavioral changes. In summary, long-term intermittent L-DOPA treatment resulted in priming of antiparkinsonian effects on improving akinesia in a rat model of severe PD. These observed changes do not mirror all aspects of motor response fluctuations in advanced PD patients and suggest differential contributions of dopaminergic treatment and lesion severity to motor complication patterns.