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: 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247115
• 关键词: Accounting; Address; Adverse effects; Advocate; Affect; Agonist; Attenuated; Behavior; Behavioral; Chronic; Clinical; Clinical Research; Corpus striatum structure; Development; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Dyskinetic syndrome; Gene Expression; Glutamates; Health; 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; 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L-DOPA的替代疗法是帕金森氏病（PD）运动症状的高效治疗方法。不幸的是，慢性L- dopa给药会诱导称为L- dopa诱导的运动障碍（LID）的异常非自愿运动，这严重影响了个人的生活质量。鉴于L-DOPA将继续是PD的主要治疗方法，因此本应用的长期目标是阐明新型机制，这些机制将改善盖子减少的药物治疗。虽然盖子的发病机理尚不清楚，但L-DOPA诱导的皮质纹状体谷氨酸释放过多，突触后纹状体DA D1受体（D1R）似乎必不可少。不幸的是，有效的抗运动障碍谷氨酸和DA受体药物疗法已证明难以捉摸和/或远离临床使用。最近的证据表明，5-HT1A受体（5-HT1AR）构成了控制盖的可行药理靶标。尽管有这些最初的发现，但5-HT1AR发挥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型的纹状体5-HT1AR机制，该机制似乎与5-HT1AR激动剂的抗抑制作用不可或缺。因此，提出的研究的中心假设是5-HT1AR刺激通过挤压DA耗尽纹状体中的皮质纹状体谷氨酸释放和D1R信号来降低盖子。该断言将使用特征良好的行为，神经化学和细胞技术进行测试。该应用的目的将通过解决3个特定目的测试以下假设来实现：1。纹状体5-HT1AR刺激减轻了盖子。 2。5-HT1AR刺激通过降低过度皮质纹状体谷氨酸释放来改善盖子。 3。5-HT1AR刺激通过减少促进盖的过度活跃的D1R信号传导机制来降低盖子。这些研究的完成将增强该领域对5-HT1A受体调节运动调节的理解，并提倡使用和改善5-HT1AR激动剂用于盖子治疗。公共卫生相关性：运动障碍帕金森氏病（PD）用药物L-DOPA有效治疗。不幸的是，长期对L-DOPA的给药会导致令人衰弱的副作用，称为运动障碍。对该应用的研究将研究一个新型的药理学靶标，该靶标有望减少运动障碍，延长L-DOPA的益处并改善PD患者的生活质量。

项目成果

Modulation of L-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus.

• 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

Serotonin transporter inhibition attenuates l-DOPA-induced dyskinesia without compromising l-DOPA efficacy in hemi-parkinsonian rats.

• DOI: 10.1111/j.1460-9568.2012.08202.x
• 发表时间: 2012-09
• 期刊: The European journal of neuroscience
• 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.

• 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

Striatal 5-HT1A receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat.

• 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

Role of the primary motor cortex in L-Dopa-induced dyskinesia and its modulation by 5-HT1A receptor stimulation.

• DOI: 10.1016/j.neuropharm.2011.05.021
• 发表时间: 2011-09
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Ostock CY;Dupre KB;Jaunarajs KL;Walters H;George J;Krolewski D;Walker PD;Bishop C
• 通讯作者: Bishop C