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

描述（由申请人提供）：多巴胺（DA）前体L-DOPA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，长期施用L-DOPA诱导异常的不自主运动，称为L-DOPA诱导的运动障碍（LID），其严重影响个体的生活质量。鉴于L-DOPA将继续作为PD的主要治疗，本申请的长期目标是阐明将改善用于减少LID的药物疗法的新机制。虽然LID的发病机制尚未完全了解，但过量的L-DOPA诱导的皮质纹状体谷氨酸释放和突触后纹状体DA D1受体（D1 R）似乎是必不可少的。不幸的是，有效的抗运动障碍的谷氨酸和DA受体药物疗法已被证明是难以捉摸的和/或远离临床应用。最近的证据表明，5-HT 1A受体（5-HT 1AR）构成了一个可行的药理学目标的控制LID。尽管有这些初步的发现，5-HT 1AR发挥其作用的机制在很大程度上是未知的。我们实验室的初步结果已经确定了一种新的纹状体5-HT 1AR机制，该机制似乎与5-HT 1AR激动剂的抗运动障碍作用不可或缺。因此，所提出的研究的中心假设是，5-HT 1AR刺激通过抑制皮质纹状体谷氨酸释放和DA耗尽纹状体中的D1 R信号传导来降低LID。这一论断将使用良好的行为，神经化学和细胞技术进行测试。本申请的目的将通过解决3个具体目标来实现，测试以下假设：1.纹状体5-HT 1AR刺激减弱LID。2. 5-HT 1AR刺激通过降低过度的皮质纹状体谷氨酸释放来改善LID。3. 5-HT 1AR刺激通过减少促进LID的过度活跃的D1 R信号传导机制来减少LID。这些研究的完成将提高该领域对5-HT 1A受体调节运动的理解，并在这样做的同时，倡导使用和改善5-HT 1AR激动剂用于LID治疗。公共卫生相关性：运动障碍帕金森氏病（PD）是有效的治疗药物左旋多巴。不幸的是，长期服用左旋多巴会导致被称为运动障碍的衰弱副作用。该应用的研究将调查一种新的药理学靶点，该靶点在减少运动障碍、延长左旋多巴的益处和改善PD患者的生活质量方面显示出希望。

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.