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

基本信息

  • 批准号:
    7800932
  • 负责人:
  • 金额:
    $ 26.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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。

项目成果

期刊论文数量(0)
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CHRISTOPHER R BISHOP其他文献

CHRISTOPHER R BISHOP的其他文献

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{{ truncateString('CHRISTOPHER R BISHOP', 18)}}的其他基金

Interrogating maladaptive serotonin raphe-striatal plasticity in L-DOPA-induced dyskinesia
探讨 L-DOPA 引起的运动障碍中血清素适应不良的中缝纹状体可塑性
  • 批准号:
    10366348
  • 财政年份:
    2021
  • 资助金额:
    $ 26.51万
  • 项目类别:
Interrogating Maladaptive Serotonin Raphe-Striatal Plasticity in L-DOPA-Induced Dyskinesia
探讨左旋多巴引起的运动障碍中血清素适应不良的中缝纹状体可塑性
  • 批准号:
    10531913
  • 财政年份:
    2021
  • 资助金额:
    $ 26.51万
  • 项目类别:
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:
    8073419
  • 财政年份:
    2008
  • 资助金额:
    $ 26.51万
  • 项目类别:
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:
    7458306
  • 财政年份:
    2008
  • 资助金额:
    $ 26.51万
  • 项目类别:
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:
    7614163
  • 财政年份:
    2008
  • 资助金额:
    $ 26.51万
  • 项目类别:
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:
    8247115
  • 财政年份:
    2008
  • 资助金额:
    $ 26.51万
  • 项目类别:
EFFECTS OF NICOTINE ON NPY FEEDING AND METABOLISM
尼古丁对 NPY 摄食和代谢的影响
  • 批准号:
    6174615
  • 财政年份:
    2000
  • 资助金额:
    $ 26.51万
  • 项目类别:
EFFECTS OF NICOTINE ON NPY FEEDING AND METABOLISM
尼古丁对 NPY 摄食和代谢的影响
  • 批准号:
    6013280
  • 财政年份:
    1999
  • 资助金额:
    $ 26.51万
  • 项目类别:

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