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.

项目摘要/摘要 激活D2和D3受体（D2R，D3R）的多巴胺激动剂，例如pramipexole，是高效的 帕金森氏病（PD）运动功能障碍的治疗。但是，经过处理的显着亚群 个体表现出冲动控制障碍（ICD）。为了建模这种现象，我们实施了一本小说 概率折现任务使用颅内自刺激（ICS）作为正增强器和 证明在类似于PD的大鼠中，慢性普拉克索增加了冒险。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 离子型谷氨酸受体（AMPAR/NMDAR）的功能。基于的机制 慢性列哌迪克尔的倾向倾向于调节奖励动机，尤其是在帕金森州，是 未知，但是吸毒领域的丰富文献表明，间接治疗 多巴胺激动剂通过增加AMPAR/NMDAR的表面表达来增强突触。将这些联系起来 将调节冲动性并保存在帕金森氏脑状态的大脑区域的概念 （例如，伏隔核，NAC）将提供有关普拉米己核引起的ICD的原因的新见解。 针对这种未满足的需求，该R21项目的总体目标是确定解剖基板和 在PD大鼠模型中，普拉克索增强冲动行为的基本机制。作为 普拉米己烯具有较高的D3R/D2R亲和力，中心假设是长期暴露于A 与治疗相关剂量的普拉辅辅剂量通过参与D3R，AKT/GSK-3途径增强了折扣 NAC中的AMPAR/NMDAR贩运，阻止这些目标将破坏折扣。这些 假设将以两个具体目标进行检验。对于特定的目标1，将使用普拉美己烯处理的慢性治疗将是 用于增强折现和给药D3R选择性拮抗剂PG01037将用于 证明D3R是必要的。我们假设PG01037，全身或直接注射 进入NAC，将阻止普拉克索引起的折扣。特定目标2将证明GSK-3 NAC中的信号传导和AMPAR/NMDAR对于普拉米己核增强折扣是必需的。我们 假设AMPAR/NMDAR表面表达将增加，PGSK-3？（不活动）将减少 NAC中GSK-3或AMPAR/NMDAR的慢性普拉哌啶和封锁将减轻普拉米克索 - 增强折扣。拟议的研究具有创新性，因为它反映了一个关于 PD中慢性D3R激活的自适应后果，以及一种验证该概念的新型模型。 这项研究很重要，因为它将大大增强我们对ICD神经病理学的理解 在多巴胺激动剂治疗PD期间。成果将为R01申请提供关键基础 对这种疗法的神经元后果的多学科，机械评估以及将来 为PD患者开发提供运动益处的PD患者的治疗方案，同时避免ICD。