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

• Published in: Journal of neurochemistry Vol. 96; no. 6; p. 1718
• Main Authors: Carta, Manolo, Lindgren, Hanna S, Lundblad, Martin, Stancampiano, Roberto, Fadda, Fabio, Cenci, M A
• Format: Journal Article
• Language: English
• Published: New York Blackwell Publishing Ltd 01-03-2006
• Subjects: Neurology; Parkinson's disease; Pharmacology; Rodents
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.03696.x

We explored possible differences in the peripheral and central pharmacokinetics ofl-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically withl-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 striatall-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection ofl-DOPA, plasmal-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels ofl-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 striatall-DOPA levels. Intrastriatal infusion ofl-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 tol-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation ofl-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability ofl-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.[PUBLICATION ABSTRACT]