Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats

Abstract

We explored possible differences in the peripheral and central pharmacokinetics of l-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with l-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatal l-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of l-DOPA, plasma l-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels of l-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal l-DOPA levels. Intrastriatal infusion of l-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response to l-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation of l-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of l-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease. © 2006 The Authors.