Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice
Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice
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DOI：
10.1073/pnas.1006511108
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发表时间：
2011-01-11
影响因子：
11.1
通讯作者：
Kang, Un Jung
中科院分区：
文献类型：
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作者：
Ding, Yunmin;Won, Lisa;Kang, Un Jung
用L-3，4-二羟基苯丙氨酸（L-DOPA）治疗帕金森病（PD）显著缓解相关的运动缺陷，但L-DOPA诱导的运动障碍（LID）随着时间的推移限制了治疗益处。先前的研究已经注意到纹状体中棘神经元的变化，包括细胞外信号调节激酶1/2（ERK）的异常激活。使用两种PD模型，传统的6-羟基多巴胺毒性损伤和黑质纹状体多巴胺能缺陷的遗传模型，我们发现，急性多巴胺挑战诱导ERK激活中多刺神经元去神经纹状体。然而，在重复L-DOPA治疗后，ERK激活在中型棘神经元中减少，而在纹状体胆碱能中间神经元中增加。ERK激活导致纹状体胆碱能神经元的基础放电率增强和对多巴胺的更强兴奋反应。ERK激活的药理学阻断剂抑制L-DOPA诱导的ERK磷酸化、神经元兴奋性和LID行为表现的变化。此外，毒蕈碱受体拮抗剂可降低LID。这些数据表明，纹状体胆碱能神经元的多巴胺敏感性增加有助于LID的表达，这表明LID的新的治疗靶点。
Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase 1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID.