Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism
Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism
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DOI：
10.1073/pnas.0711839105
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发表时间：
2008-02-12
影响因子：
11.1
通讯作者：
Svenningsson, Per
中科院分区：
文献类型：
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作者：
Zhang, Xiaoqun;Andren, Per E.;Svenningsson, Per
帕金森病（PD）的特征是黑质多巴胺能神经元投射到纹状体的进行性变性。通过左旋多巴恢复多巴胺传递可缓解PD症状，但会引起显著的副作用。PD患者的纹状体中存在着较强的5-羟色胺能神经支配，这种神经支配在PD患者中相对保留。对这种神经支配的研究在很大程度上被忽视了。在这里，我们表明，长期L-DOPA管理6-OHDA损伤的啮齿动物增加，通过D-1受体，5-HT 1B受体及其衔接蛋白，p11，多巴胺去神经纹状体黑质神经元的水平。使用单侧6-OHDA损伤的p11 WT和KO小鼠，发现给予选择性5-HT 1B受体激动剂CP 94253以p11依赖的方式抑制L-DOPA诱导的旋转行为和异常不自主运动。这些数据揭示了左旋多巴诱导的负反馈机制，由此5-羟色胺系统可能会影响帕金森综合征的病理学。
Parkinson's disease (PD) is characterized by a progressive degeneration of substantia nigra dopaminergic neurons projecting to the striatum. Restoration of dopamine transmission by L-DOPA relieves symptoms of PD but causes prominent side effects. There is a strong serotonin innervation of the striatum by serotonergic neurons that remains relatively preserved in PD. The study of this innervation has been largely neglected. Here, we demonstrate that chronic L-DOPA administration to 6-OHDA-lesioned rodents increases, via D-1 receptors, the levels of the 5-HT1B receptor and its adaptor protein, p11, in dopamine-denervated striatonigral neurons. Using unilaterally 6-OHDA-lesioned p11 WT and KO mice, it was found that administration of a selective 5-HT1B receptor agonist, CP94253, inhibited L-DOPA-induced rotational behavior and abnormal involuntary movements in a p11-dependent manner. These data reveal an L-DOPA-induced negative-feedback mechanism, whereby the serotonin system may influence the symptomatology of Parkinsonism.