MOTOR FLUCTUATIONS IN LEVODOPA TREATED PARKINSONIAN RATS - RELATION TO LESION EXTENT AND TREATMENT DURATION

The pathogenesis of the motor fluctuations that complicate levodopa tr eatment of most parkinsonian patients remains uncertain. To evaluate t he contribution of the degree of dopamine neuron loss and the duration of levodopa exposure, rats whose nigrostriatal system had been previo usly lesioned unilaterally by 6-hydroxydopamine received twice daily l evodopa (25 mg/kg) injections for three weeks. The magnitude of the ro tational response to levodopa more than doubled during the first week of treatment (P < 0.01), but remained essentially constant thereafter. Rats with over 95 percent loss of dopaminergic neurons evidenced a pr ogressive shortening in the duration of levodopa's motor effects (P < 0.01) as well as a failure of nearly 8 percent of levodopa injections to elicit any response after the first week of treatment. In contrast, response changes resembling those associated with end of dose deterio ration and on-off fluctuations in parkinsonian patients did not occur in the less severely lesioned rats. These results suggest that the ext ent of a dopamine neuron loss must exceed a relatively high threshold before intermittent levodopa treatment produces changes favoring the r apid appearance of motor fluctuations of the wearing-off and on-off ty pes.