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. The dopamine (DA) precursor, L-DOPA, is still the mainstay of the treatment of Parkinson's disease (PD). Unfortunately, after a few years from treatment initiation, L-DOPA loses its ability to provide a stable symptomatic control, and most patients start to exhibit pronounced oscillations in mobility ('wearing-off' and 'on-off' fluctuations) and abnormal involuntary movements (dyskinesia) (for review see Marsden et al. 1981;Nutt 1992). There is ample agreement that dyskinesias and complex, unpredictable fluctuations are caused by plastic changes produced by L-DOPA downstream of the nigrostriatal DA neuron (Chase 1998;Obeso et al. 2004). This contention is strongly supported by findings obtained in 6-hydroxydopamine (6-OHDA) lesioned rats treated with L-DOPA. In this animal model, the development of dyskinesia is positively correlated with gene and protein expression changes in striatal neurons, and shows a less tight, non-linear relationship with the extent of nigral DA cell loss (Cenci 2002;Winkler et al. 2002). Interestingly, rats with the same degree of DA denervation, and receiving the same dose of L-DOPA, may show a large variability in developing dyskinesia and the associated plastic changes (Andersson et al. 1999;Winkler et al. 2002;Picconi et al. 2003). This variability suggests that some DA-denervated subjects are relatively protected from the dyskinetic action of L-DOPA by some yet unknown...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.