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

被引:125
作者
Carta, M
Lindgren, HS
Lundblad, M
Stancampiano, R
Fadda, F
Cenci, MA
机构
[1] Lund Univ, Basal Ganglia Pathophysiol Unit, Dept Exp Med Sci, S-22184 Lund, Sweden
[2] Univ Cagliari, Sez Fisiol & Nutr Umana, Dipartimento Sci Applicate Biosistemi, Cagliari, Italy
关键词
dyskinesia; 5-HT; microdialysis; Parkinson's disease; striatum;
D O I
10.1111/j.1471-4159.2006.03696.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1718 / 1727
页数:10
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