Brain signaling effects of pramipexole-induced impulsivity in parkinsonian rats

普拉克索诱发帕金森病大鼠冲动的脑信号传导效应

• 批准号: 8693369
• 负责人: T. Celeste Napier
• 金额: $ 24.14万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693369
• 关键词: Acute; Affinity; Agonist; Animal Model; Behavior; Binge Eating; Biochemistry; Brain; Brain region; Cell surface; Chemicals; Chronic; Clinical; Corpus striatum structure; DRD2 gene; Data; Disease; Dopamine; Dopamine Agonists; Dose; Drug Addiction; Evaluation; Exhibits; Exposure to; Foundations; Functional disorder; Future; Glutamate Receptor; Glutamates; Glycogen Synthase Kinase 3; Goals; Impulse Control Disorders; Impulsive Behavior; Impulsivity; Individual; Injection of therapeutic agent; Lesion; Link; Literature; Mediating; Membrane; Modeling; Molecular; Motivation; Motor; Neurobiology; Neuronal Plasticity; Neurons; Nucleus Accumbens; Obsessive compulsive behavior; Outcome; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathological Gambling; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Positive Reinforcer; Probability; Protocols documentation; Publishing; Rattus; Reporting; Research; Restless Legs Syndrome; Rewards; Risk-Taking; Role; Saline; Self Stimulation; Signal Pathway; Signal Transduction; Site; Staging; Surface; Synapses; Tardive Dyskinesia; Testing; Therapeutic; Tissues; Training; Work; base; discounting; effective therapy; indexing; innovation; insight; motor deficit; multidisciplinary; nervous system disorder; neuromechanism; neuropathology; novel; novel therapeutics; osmotic minipump; pramipexol; public health relevance; receptor; receptor expression; research study; subcutaneous; therapeutic development; trafficking

PROJECT SUMMARY/ABSTRACT Dopamine agonists that activate D2 and D3 receptors (D2R, D3R), e.g., pramipexole, are highly effective therapy for the motor dysfunction of Parkinson's disease (PD). However, a significant subpopulation of treated individuals exhibit impulse control disorders (ICDs). To model this phenomenon, we implemented a novel probability discounting task using intracranial self-stimulation (ICSS) as the positive reinforcer and demonstrated that in PD-like rats, chronic pramipexole increases risk-taking. Emerging are the concepts that D2R/D3R activation engages the Akt/GSK-3¿ signaling pathway, and this cascade is involved in the trafficking and function of ionotropic glutamate receptors (AMPAR/NMDAR). The mechanisms that underlie the propensity of chronic pramipexole to dysregulate reward-motivation, especially in the parkinsonian state, are unknown, but the rich literature from the drug addiction field demonstrates that chronic treatment with indirect dopamine agonists strengthen synapses by increasing surface expression of AMPAR/NMDAR. Linking these concepts together for brain regions that regulate impulsivity, and are preserved in the parkinsonian brain state (e.g., the nucleus accumbens, NAc), will provide new insights into the cause of pramipexole-induced ICDs. Targeting this unmet need, the overall objective of this R21 project is to identify the anatomical substrates and underlying mechanisms by which pramipexole enhances impulsive behavior in a rat model of PD. As pramipexole has a high D3R/D2R affinity ratio, the central hypotheses are that chronic exposure to a therapeutically relevant dose of pramipexole enhances discounting by engaging D3R, Akt/GSK-3¿ pathways and AMPAR/NMDAR trafficking in the NAc, and blocking these targets will disrupt discounting. These hypotheses will be tested in two Specific Aims. For Specific Aim 1, chronic treatment with pramipexole will be used to enhance discounting, and administration of a D3R-selective antagonist, PG01037, will be used to demonstrate that D3R are necessary. We hypothesize that PG01037, given systemically or directly injected into the NAc, will block pramipexole-induced discounting. Specific Aim 2 will demonstrate that GSK-3 signaling and AMPAR/NMDAR in the NAc are necessary for pramipexole-enhanced discounting. We hypothesize that AMPAR/NMDAR surface expression will increase, and pGSK-3¿ (inactive) will decrease after chronic pramipexole and blockade of GSK-3 or AMPAR/NMDAR in the NAc will mitigate pramipexole- enhanced discounting. The proposed research is innovative because it reflects a novel concept regarding the adaptive consequence of chronic D3R activation in PD, and a novel model in which to validate this concept. The research is significant because it will substantially enhance our understanding of ICD neuropathology during dopamine agonist therapy for PD. Outcomes will provide a critical foundation for an R01 application for multidisciplinary, mechanistic evaluations of the neuronal consequences of such therapy, and for future development of therapeutic protocols for PD patients that provide motor benefits while avoiding ICDs.

项目概要/摘要 激活 D2 和 D3 受体（D2R、D3R）的多巴胺激动剂（例如普拉克索）非常有效 帕金森病（PD）运动功能障碍的治疗。然而，接受治疗的一个重要亚群 个体表现出冲动控制障碍（ICD）。为了模拟这种现象，我们实施了一种新颖的 使用颅内自我刺激（ICSS）作为正强化物的概率贴现任务 研究表明，在 PD 样大鼠中，长期服用普拉克索会增加冒险行为。新兴的概念 D2R/D3R 激活参与 Akt/GSK-3¿ 信号通路，并且该级联参与贩运 和离子型谷氨酸受体 (AMPAR/NMDAR) 的功能。其背后的机制 慢性普拉克索导致奖赏动机失调的倾向，特别是在帕金森状态下， 未知，但来自毒瘾领域的丰富文献表明，间接慢性治疗 多巴胺激动剂通过增加 AMPAR/NMDAR 的表面表达来增强突触。链接这些 调节冲动的大脑区域的概念在一起，并保留在帕金森大脑状态中 （例如伏隔核，NAc）将为普拉克索诱发 ICD 的病因提供新的见解。 针对这一未满足的需求，R21 项目的总体目标是确定解剖基质和 普拉克索增强 PD 大鼠模型冲动行为的潜在机制。作为 普拉克索具有高 D3R/D2R 亲和力比，中心假设是长期暴露于 治疗相关剂量的普拉克索通过参与 D3R、Akt/GSK-3¿ 途径增强折扣 和 AMPAR/NMDAR 在 NAc 中的贩运，阻止这些目标将扰乱折扣。这些 假设将在两个具体目标中进行测试。对于具体目标 1，普拉克索的长期治疗将是 用于增强折扣，并且 D3R 选择性拮抗剂 PG01037 的给药将用于 证明D3R是必要的。我们假设 PG01037 全身给药或直接注射 进入NAc，将阻止普拉克索引起的折扣。具体目标 2 将证明 GSK-3 NAc 中的信号传导和 AMPAR/NMDAR 对于普拉克索增强折扣是必需的。我们 假设 AMPAR/NMDAR 表面表达会增加，并且 pGSK-3¿（无活性）会减少 慢性普拉克索和 NAc 中 GSK-3 或 AMPAR/NMDAR 阻断将减轻普拉克索- 加强折扣。所提出的研究具有创新性，因为它反映了关于 PD 中慢性 D3R 激活的适应性后果，以及验证这一概念的新模型。 这项研究意义重大，因为它将大大增强我们对 ICD 神经病理学的理解 多巴胺激动剂治疗 PD 期间。结果将为 R01 申请提供重要基础 对此类治疗的神经元后果进行多学科、机制评估，并为未来做好准备 为 PD 患者制定治疗方案，在避免使用 ICD 的同时提供运动益处。