Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats
Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats
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DOI：
10.1111/j.1471-4159.2006.03696.x
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发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Cenci, MA
中科院分区：
文献类型：
--
作者：
Carta, M;Lindgren, HS;Cenci, MA
我们探讨了外周和中枢左旋多巴的药代动力学可能存在的差异，作为运动障碍易感性个体差异的基础。单侧，6-羟基多巴胺（6-OHDA）损伤的大鼠长期与左旋多巴诱导和监测异常不自主运动（AIM）。运动障碍和非运动障碍的情况下，然后进行比较方面的血浆和纹状体左旋多巴浓度，组织水平的多巴胺（DA），DA代谢产物，和5-羟色胺。单次腹腔注射L-DOPA后，运动障碍和非运动障碍动物的血浆L-DOPA浓度没有差异，而纹状体细胞外液中L-DOPA的峰值水平约为后者的5倍。有趣的是，AIM的时间进程与纹状体L-DOPA水平的激增相一致。在所有6-OHDA损伤的大鼠中，无论先前是否引发运动障碍，通过反向透析浓度依赖性纹状体内输注L-DOPA均诱导AIM。稳态水平的DA及其代谢产物在纹状体和皮质组织之间没有不同的运动障碍和非运动障碍的动物，这表明所观察到的运动反应L-DOPA的差异并不依赖于病变引起的DA耗竭的程度。这些结果表明，纹状体细胞外液中左旋多巴水平的升高是运动障碍发生的必要和充分条件。左旋多巴中枢生物利用度的个体差异可能为帕金森病运动障碍易感性的变化提供线索。
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.