左旋多巴是治疗帕金森病（PD）最有效的方法，但长期左旋多巴治疗后出现的异动症（LID）严重影响患者的生活质量。在前期我们研究发现D1R超敏在LID的发生机制过程中扮演着重要的角色，且与DARPP32/PKA/ERK信号通路活性改变有关。β-arrestin2可以将D1R脱敏产生抗异动症的作用，然而对β-arrestin2 参与 LID的机制研究很少。本课题拟探讨β-arrestin2通过影响D1R信号通路活性参与LID的发生机制，包括动物行为学、受体表达、信号转导的不同层面。通过观察β-arrestin2在LID发生过程中的表达变化，了解其与 D1R 共同表达情况。分别过表达和基因沉默β-arrestin2观察大鼠行为学及D1R表达和信号通路的改变。最后探究β-arrestin2 影响 LID 的症状能否被 D1R 所逆转，及其下游信号通路的变化，为开发治疗LID的药物提供理论基础。

Levodopa (L-dopa) is the gold standard for symptomatic treatment of Parkinson’s disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). The management of LIDs is an ongoing challenge in PD treatment. Since the neurobiological mechanisms of LIDs remain unclear, clinical pharmacologically intervention is restricted. Our previous studies indicate that LID is associated with sensitized D1R transmission located on the medium spiny neurons (MSNs) of the direct striatonigral pathway. Sensitized D1R transmission may also results in augmented synthesis of DARPP32/PKA/ERK. Meanwhile, previous studies demonstrated that β-arrestin2 desensitized G protein signaling at D1R and initiates receptor endocytosis or internalization. In this study, we aim to investigate β-arrestin2 in the treatment of L-dopa–induced dyskinesia via D1R signal pathway. To begin with, detect the distribution and level of β-arrestin2, and immunofluorescence used to detect the co-expression of β-arrestin2 and D1R. Then, we will explore the influence of viral rescue or overexpression of β-arrestin2 in terms of the behavior alteration and its key biochemical markers. In addition, genetic deletion of β-arrestin2 whether or not can markedly enhancing the dyskinesia-like effects of chronic L-dopa treatment is also need to be proved? Finally, we want to test the results of modulate β-arrestin2 in the treatment of L-dopa–induced dyskinesia can be reversed by D1R agonists or antagonists. This study will further explain the mechanism of LIDs and provide theory evidences for β-arrestin2 modulator therapy for Parkinson’s disease with dyskinesia.