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，如普拉克索，是非常有效的 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)。为了模拟这一现象，我们实现了一种新的 以颅内自我刺激(ICSS)为正强化的概率贴现作业 证明在帕金森病样大鼠中，慢性普拉克索增加了冒险行为。正在出现的概念是 D2R/D3R激活参与Akt/GSK-3信号通路，这一级联反应参与运输 和离子型谷氨酸受体(AMPAR/NMDAR)的功能。这些机制构成了 慢性普拉克索失调奖赏动机的倾向，特别是在帕金森状态下，是 未知，但来自药物成瘾领域的丰富文献表明，慢性治疗与间接 多巴胺激动剂通过增加AMPAR/NMDAR的表面表达来增强突触。将这些链接起来 调节冲动的大脑区域的概念一起，并保存在帕金森病患者的大脑状态中 (例如，伏隔核，NAC)，将为普拉克索诱发ICD的原因提供新的见解。 针对这一未得到满足的需求，该R21项目的总体目标是确定解剖基础和 普拉克索增强帕金森病大鼠模型冲动行为的潜在机制。AS 普拉克索有很高的D3R/D2R亲和力比率，中心假设是长期接触A 治疗相关剂量的普拉克索通过参与D3R、Akt/GSK-3？通路提高折扣 和AMPAR/NMDAR在NAC的贩运，阻止这些目标将扰乱折扣。这些 假说将在两个具体目标上进行检验。对于特定目标1，使用普拉克索的慢性治疗将是 用于提高折扣，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，全身注射或直接注射 进入NAC，将阻止普拉克索诱导的折扣。《特定目标2》将证明GSK-3 NAC中的信号和AMPAR/NMDAR是普拉克索增强折扣所必需的。我们 假设AMPAR/NMDAR表面表达增加，而pGSK-3？(无效)在 慢性普拉克索和阻断NAC中GSK-3或AMPAR/NMDAR将缓解普拉克索。 更强的折扣。这项拟议的研究具有创新性，因为它反映了关于 慢性D3R激活在帕金森病中的适应性后果，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 在多巴胺激动剂治疗帕金森病期间。结果将为R01应用程序提供关键基础 对这种治疗的神经元后果的多学科、机械性评估以及对未来的评估 为帕金森病患者开发治疗方案，在避免ICD的同时提供运动益处。