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Role of striatal l ‐DOPA in the production of dyskinesia in 6‐hydroxydopamine lesioned rats
Author(s) -
Carta Manolo,
Lindgren Hanna S.,
Lundblad Martin,
Stancampiano Roberto,
Fadda Fabio,
Cenci M. A.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03696.x
Subject(s) - hydroxydopamine , dyskinesia , oxidopamine , neuroscience , psychology , parkinson's disease , dopamine , medicine , dopaminergic , substantia nigra , disease
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.