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

5-HT1A 受体机制调节 L-DOPA 诱导的运动障碍

• 批准号: 7800932
• 负责人: CHRISTOPHER R BISHOP
• 金额: $ 26.51万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7800932
• 关键词: Accounting; Address; Adverse effects; Advocate; Affect; Agonist; Attenuated; Behavior; Behavioral; Chronic; Clinical; Clinical Research; Corpus striatum structure; Development; Dopa; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Dyskinetic syndrome; Gene Expression; Glutamates; Immunohistochemistry; In Situ Hybridization; Individual; L-DOPA induced dyskinesia; Laboratories; Levodopa; Mediating; Messenger RNA; Microdialysis; Microinjections; Mitogen-Activated Protein Kinases; Motor; Movement; Movement Disorders; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuronal Plasticity; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphorylation; Population; Positioning Attribute; Quality of life; Rattus; Receptor Signaling; Regulation; Replacement Therapy; Research; Role; Serotonin; Serotonin Receptor 5-HT1A; Signal Transduction; Site; Symptoms; Synapses; Techniques; Testing; abnormal involuntary movement; aspartate receptor; effective therapy; improved; in vivo; neurochemistry; novel; pre-clinical; pre-prodynorphin; public health relevance; receptor

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.

描述（由申请人提供）：多巴胺（DA）前体左旋多巴（L-DOPA）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，长期施用左旋多巴会引起异常的不自主运动，称为左旋多巴诱发的运动障碍(LID)，这严重影响个体的生活质量。鉴于L-DOPA将继续作为PD的主要治疗方法，本申请的长期目标是阐明将改善减少LID的药物治疗的新机制。虽然 LID 的发病机制尚不清楚，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 (D1R) 似乎至关重要。不幸的是，有效的抗运动障碍谷氨酸和DA受体药物疗法已被证明难以捉摸和/或远未达到临床应用。最近的证据表明，5-HT1A 受体 (5-HT1AR) 构成了控制 LID 的可行药理学靶点。尽管有这些初步发现，但 5-HT1AR 发挥作用的机制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 激动剂的抗运动障碍作用不可或缺的一部分。因此，本研究的中心假设是，5-HT1AR 刺激通过抑制 DA 耗尽纹状体中的皮质纹状体谷氨酸释放和 D1R 信号传导来减少 LID。这一断言将使用特征明确的行为、神经化学和细胞技术进行测试。本应用的目标将通过解决测试以下假设的 3 个具体目标来实现： 1. 纹状体 5-HT1AR 刺激减弱 LID。 2. 5-HT1AR 刺激通过降低皮质纹状体谷氨酸的过度释放来改善 LID。 3. 5-HT1AR 刺激通过减少促进 LID 的过度活跃的 D1R 信号传导机制来减少 LID。这些研究的完成将增强该领域对 5-HT1A 受体运动调节的理解，从而倡导使用和改进 5-HT1AR 激动剂用于 LID 治疗。公众健康相关性：运动障碍帕金森病 (PD) 可通过左旋多巴药物有效治疗。不幸的是，长期服用左旋多巴会导致使人衰弱的副作用，称为运动障碍。该应用的研究将调查一种新的药理学靶点，该靶点有望减少帕金森病患者的运动障碍、延长左旋多巴的疗效并改善其生活质量。