Regulation of L-DOPA-induced dyskinesia by 5-HT1A receptor mechanisms

描述(申请人提供)：多巴胺(DA)前体L-多巴的替代疗法是治疗帕金森病(PD)运动症状的高效疗法。不幸的是，长期服用L多巴会引起异常的不自主运动，称为L多巴诱发的运动障碍(LID)，严重影响个体的生活质量。鉴于L-多巴仍将是帕金森病的主要治疗方法，本申请的长期目标是阐明新的机制，以改进药物治疗以减少LID。虽然LID的发病机制尚不清楚，但L-多巴诱导的皮质纹状体谷氨酸过度释放和突触后纹状体DA D_1受体(D1R)似乎是必不可少的。不幸的是，有效的抗运动障碍谷氨酸和DA受体药物疗法已经被证明是难以捉摸的和/或离临床应用很远。最近的证据表明，5-HT1A受体(5-HT1AR)是控制LID的一个可行的药理靶点。尽管有这些初步发现，但5-HT1AR发挥作用的机制(S)在很大程度上尚不清楚。我们实验室的初步结果已经确定了一种新的纹状体5-HT1AR机制，该机制似乎是5-HT1AR激动剂抗动力作用的组成部分。因此，这项研究的中心假设是，5-HT1AR刺激通过抑制纹状体皮质谷氨酸的释放和DA缺乏的纹状体中的D1R信号来减少LID。这一断言将使用具有良好特征的行为、神经化学和细胞技术进行测试。这项应用的目的将通过解决3个特定的目的来检验以下假设：1.纹状体5-HT1AR刺激可减弱LID。2.刺激5-HT1AR可通过减少皮质纹状体谷氨酸的过量释放而改善LID。3.刺激5-HT1AR通过减少促进LID的过度活跃的D1R信号机制来减少LID。这些研究的完成将加强该领域对5-HT1a受体运动调节的了解，从而倡导使用和改进5-HT1AR激动剂治疗LID。公共卫生意义：运动障碍帕金森氏病(PD)是一种有效的药物L-多巴。不幸的是，长期服用L多巴会导致身体虚弱的副作用，称为运动障碍。对这一应用的研究将探索一种新的药理靶点，该靶点有望减少运动障碍，延长L-多巴的疗效，并改善帕金森病患者的生活质量。

DESCRIPTION (provided by applicant): Replacement therapy with the dopamine (DA) precursor L-DOPA is a highly effective treatment for the motor symptoms of Parkinson's disease (PD). Unfortunately, chronic L- DOPA administration induces abnormal involuntary movements termed L-DOPA- induced dyskinesia (LID), which severely impacts the quality of life for the individual. Given that L-DOPA will continue to be the primary treatment for PD, the long-term objective of the present application is to elucidate novel mechanisms that will improve pharmacotherapy for the reduction of LID. While the pathogenesis of LID is not well understood, excessive L-DOPA-induced corticostriatal glutamate release and post- synaptic striatal DA D1 receptors (D1R) appear essential. Unfortunately, effective anti- dyskinetic glutamate and DA receptor pharmacotherapies have proven elusive and/or far from clinical use. Recent evidence indicates that 5-HT1A receptors (5-HT1AR) constitute a viable pharmacological target for the control of LID. Despite these initial findings, the mechanism(s) by which 5-HT1AR exert their effects is largely unknown. Preliminary results from our laboratory have identified a novel striatal 5-HT1AR mechanism that appears integral to the anti-dykinetic effects of 5-HT1AR agonists. Therefore, the central hypothesis of the proposed research is that 5-HT1AR stimulation reduces LID by squelching corticostriatal glutamate release and D1R signaling in the DA-depleted striatum. This assertion will be tested using well-characterized behavioral, neurochemical and cellular techniques. The objective of this application will be accomplished by addressing 3 specific aims testing the following hypotheses: 1. Striatal 5-HT1AR stimulation attenuates LID. 2. 5-HT1AR stimulation ameliorates LID by lowering excessive corticostriatal glutamate release. 3. 5-HT1AR stimulation reduces LID by lessening overactive D1R signaling mechanisms that promote LID. Completion of these studies will enhance the field's understanding of 5-HT1A receptor regulation of movement and in so doing, advocate the use and improvement of 5-HT1AR agonists for LID treatment. PUBLIC HEALTH RELEVANCE: The movement disorder Parkinson's disease (PD) is effectively treated with the drug L-DOPA. Unfortunately chronic administration of L-DOPA leads to debilitating side effects known as dyskinesia. Studies of this application will investigate a novel pharmacologic target that shows promise in reducing dyskinesia, prolonging L-DOPA's benefit and improving the quality of life for the PD patient.