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

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
负责人:
CHRISTOPHER R BISHOP
金额:
$26.24万
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
已结题
起止时间:
2008-05-01 至 2014-04-30

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中文摘要
翻译
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。
英文摘要
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.
期刊论文(20)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1016/j.neuropharm.2015.03.008
发表时间: 2015-08
期刊: Neuropharmacology
影响因子: 4.7
作者: [Ostock CY, Hallmark J, Palumbo N, Bhide N, Conti M, George JA, Bishop C]
通讯作者: Bishop C
DOI: 10.1111/j.1460-9568.2012.08202.x
发表时间: 2012-09
期刊: The European journal of neuroscience
影响因子: --
作者: [Bishop C, George JA, Buchta W, Goldenberg AA, Mohamed M, Dickinson SO, Eissa S, Eskow Jaunarajs KL]
通讯作者: Eskow Jaunarajs KL
Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats.
长时间选择性5-羟色胺再摄取抑制对Hemi-Parkinsonian大鼠L- dopa诱导的运动障碍的发育和表达的影响。
DOI: 10.1016/j.neuropharm.2013.09.017
发表时间: 2014-02
期刊: Neuropharmacology
影响因子: 4.7
作者: [Conti MM, Ostock CY, Lindenbach D, Goldenberg AA, Kampton E, Dell'isola R, Katzman AC, Bishop C]
通讯作者: Bishop C
DOI: 10.1016/j.neuropharm.2008.08.031
发表时间: 2008-12
期刊: Neuropharmacology
影响因子: 4.7
作者: [Dupre KB, Eskow KL, Barnum CJ, Bishop C]
通讯作者: Bishop C
15
    Interrogating maladaptive serotonin raphe-striatal plasticity in L-DOPA-induced dyskinesia
    • 批准号:
      10366348
    • 项目类别:
    • 资助金额:
      $69.0万
    • 财政年份:
      2021
    • 负责人:
      CHRISTOPHER R BISHOP
    • 依托单位:
    Interrogating Maladaptive Serotonin Raphe-Striatal Plasticity in L-DOPA-Induced Dyskinesia
    • 批准号:
      10531913
    • 项目类别:
    • 资助金额:
      $65.12万
    • 财政年份:
      2021
    • 负责人:
      CHRISTOPHER R BISHOP
    • 依托单位:
    Regulation of L-DOPA-induced dyskinesia by 5-HT1A receptor mechanisms
    • 批准号:
      8073419
    • 项目类别:
    • 资助金额:
      $26.24万
    • 财政年份:
      2008
    • 负责人:
      CHRISTOPHER R BISHOP
    • 依托单位:
    Regulation of L-DOPA-induced dyskinesia by 5-HT1A receptor mechanisms
    • 批准号:
      7458306
    • 项目类别:
    • 资助金额:
      $25.65万
    • 财政年份:
      2008
    • 负责人:
      CHRISTOPHER R BISHOP
    • 依托单位:
    海外基金