Department of Neurology, University of Chicago, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):840-5. doi: 10.1073/pnas.1006511108. Epub 2010 Dec 27.
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 kinase1/2 (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.
用 L-3,4-二羟苯丙氨酸（L-DOPA）治疗帕金森病（PD）可显著缓解相关运动障碍，但 L-DOPA 诱导的运动障碍（LID）会随着时间的推移限制治疗效果。先前的研究注意到纹状体中型多棘神经元的变化，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，即传统的 6-羟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刺激会诱导去神经纹状体中型多棘神经元中的 ERK 激活。然而，经过反复的 L-DOPA 治疗后，中型多棘神经元中的 ERK 激活减少，而纹状体胆碱能中间神经元中的 ERK 激活增加。ERK 激活导致纹状体胆碱能神经元的基础放电率增加，对多巴胺的兴奋性反应增强。ERK 激活的药理学抑制剂可抑制 L-DOPA 诱导的 ERK 磷酸化、神经元兴奋性和 LID 的行为表现的变化。此外，毒蕈碱受体拮抗剂可减少 LID。这些数据表明，纹状体胆碱能神经元对多巴胺的敏感性增加导致了 LID 的表达，这提示了 LID 的新的治疗靶点。
