Dose-related effects of continuous levodopa infusion in rats with unilateral lesions of the substantia nigra

Preclinical studies in rats have demonstrated markedly different effects of intermittent and continuous levodopa administration on many biochemical and functional parameters yet the dose regimens employed have not been fully evaluated. In this study, rats with unilateral 6-hydroxydopamine nigral lesions were administered levodopa (0-1200 mg/kg/day) and benserazide (25 mg/kg/day) subcutaneously via osmotic minipump and studied 20-22 h later for rotational behavior, striatal dopamine-concentration, and regional cerebral glucose utilization (RCGU). Levodopa infusion at 100 mg/kg/day resulted in minimal rotation and minimal striatal dopamine replacement but did increase RCGU in the subthalamic nucleus and decrease RCGU in the lateral habenula, consistent with a selective inhibition of the striatopallidal GABAergic (indirect striatal output) pathway. Levodopa infusion at 100 mg/kg/day did not significantly increase RCGU in the entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), as does the acute injection of levodopa (25-50 mg/kg), indicating that this levodopa dose elicits only part of the spectrum of metabolic effects elicited by acute levodopa injection. Higher doses of levodopa (400-1200 mg/kg/day) resulted in moderate rates of rotation, dose-dependent increases in striatal dopamine, and increased RCGU in the EP and SNr, consistent with activation of the striatonigral GABAergic (direct striatal output) pathway. In the EP and SNr, the two major output nuclei of the basal ganglia, levodopa infusion at 800 and 1200 mg/kg/day reproduced the metabolic effects elicited by acute injection of levodopa. These results demonstrate, for the first time, dose-dependent effects of levodopa on distinct populations of striatal output neurons which may be relevant to the pathogenesis of levodopa-induced dyskinesias in Parkinson's disease. The minimal dopamine replacement and partial functional effects elicited by levodopa infusion at 100 mg/kg/day indicate the need for caution in the interpretation of prior studies of continuous levodopa infusion which employed this dose.