Role of D3 receptors in drug-induced impulsivity in a rat model of Parkinson's di

D3 受体在帕金森病大鼠模型药物诱导冲动中的作用

• 批准号: 8535070
• 负责人: Stephanie E Tedford
• 金额: $ 4.22万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535070
• 关键词: AMPA Receptors; Adverse effects; Affect; Agonist; Animal Model; Attenuated; Behavior; Behavioral; Binge Eating; Brain; Brain region; Cell surface; Chronic; Complement; Corpus striatum structure; Development; Dopamine Agonists; Dose; Experimental Designs; Fellowship; Forelimb; Functional disorder; Future; Glutamates; Goals; Human; Impulse Control Disorders; Impulsivity; Instruction; Knowledge; Laboratories; Laboratory Animals; Lead; Learning; Lesion; Life; Link; Lithium; Measures; Mediating; Mental Health; Mission; Modeling; Motor; Movement Disorders; National Research Service Awards; Nature; Neurobiology; Neuronal Plasticity; Outcome; Oxidopamine; Parkinson Disease; Pathological Gambling; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Positioning Attribute; Positive Reinforcer; Postdoctoral Fellow; Pre-Clinical Model; Probability; Protocols documentation; Public Health; Rattus; Receptor Activation; Receptor Signaling; Research; Research Personnel; Research Project Grants; Restless Legs Syndrome; Rewards; Risk-Taking; Rodent; Role; Self Stimulation; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Surface; Synapses; Synaptic plasticity; Techniques; Testing; Training; Training Programs; Translational Research; Treatment Efficacy; Valproic Acid; Western Blotting; Work; addiction; career; discounting; dopamine D3 receptor; dopamine system; experience; improved; innovation; motor deficit; motor disorder; multidisciplinary; neuropathology; novel; pramipexol; prevent; receptor; skills; statistics; trafficking

DESCRIPTION (provided by applicant): This NRSA application is for support of my graduate training, including a translational research project focused on impulse control disorders (ICDs) in Parkinson's disease (PD). Pramipexole (PPX) is a dopamine (DA) D3 receptor (D3R)-preferring agonist used to treat motor dysfunctions in PD. A significant subset of treated patients (e.g., 13.6%1) develop ICDs, i.e., behavioral addictions like pathological gambling, hypersexuality, compulsive shopping and binge eating. Our lab has established a novel probability discounting task in rats that measures "risk-taking" by using intracranial self-stimulation (ICSS) as the positive reinforcer. Using this model, I plan to ascertain the role of the D3R in PPX-induced discounting. Thereafter, I plan to determine if the D3R-mediated effects involve intracellular mechanisms that are known to regulate learning as well as drug/behavioral addictions, i.e., trafficking of the glutamatergic receptor AMPA. Accordingly, my overall hypotheses are that D3R activation by PPX leads to increased risk-taking, which may be more pronounced in PD-like rats due to dysregulated dopamine systems, and that the neurobiology of this effect involves D3R-mediated increases in surface expression of AMPA receptors (Rs) in brain regions that govern impulsivity. I propose three Specific Aims to test these hypotheses. Rats with 6-hydroxydopamine-induced lesions of the dorsolateral striatum and controls will be tested. The Napier lab has already demonstrated that these PD-like rats acquire and perform ICSS-mediated probability discounting. In Aim 1, I will evaluate the effects of PPX at a low dose suprathreshold to improving motor deficits in the forelimb step task in the probability discounting task. It is my prediction that PPX will enhance risk-taking in PD-like rats, but not in control rat due to increased vulnerability of the PD brain state. In Aim 2, I will co-administer selective D3R antagonists with PPX, and predict that development and expression of PPX-induced risk-taking will be blocked. In Aim 3, I will evaluate D3R-mediated cell signaling that governs synaptic plasticity. I propose that D3R activation enhances AMPAR trafficking to the cell surface through an Akt/GSK-3b signaling pathway. I will assess the effects of PPX treatment on surface expression of AMPARs, as well as levels of activated Akt and GSK-3b signaling using a modified Western blot protocol ongoing in the Napier lab. I predict an increase in the efficacy of this signaling pathway in PD-like rats. In summary, this training opportunity will allow me to use a novel preclinical model of ICDs to pioneer the signal transduction pathways that are associated with PPX- induced risk-taking behaviors. Therefore, my extensive training not only will include highly sophisticated techniques, but experimental design for a wide range of applications. This exciting research, along with my training program, will provide me all the necessary skill sets for a future career in medications development for neuropathologies, especially those where diseases of motor function co-occur with dysregulation of mental health.

描述（由申请人提供）：此 NRSA 申请是为了支持我的研究生培训，包括一个专注于冲动控制障碍 (ICD) 的转化研究项目 帕金森病（PD）。普拉克索 (PPX) 是一种多巴胺 (DA) D3 受体 (D3R) 优先激动剂，用于治疗 PD 运动功能障碍。接受治疗的患者中有很大一部分（例如 13.6%1）患有 ICD，即行为成瘾，如病理性赌博、性欲亢进、强迫性购物和暴饮暴食。我们的实验室在大鼠中建立了一种新颖的概率贴现任务，通过使用颅内自我刺激（ICSS）作为正强化物来测量“冒险”行为。我计划使用这个模型来确定 D3R 在 PPX 引起的折扣中的作用。此后，我计划确定 D3R 介导的效应是否涉及已知调节学习以及药物/行为成瘾的细胞内机制，即谷氨酸能受体 AMPA 的运输。因此，我的总体假设是，PPX 激活 D3R 会导致冒险行为增加，这在 PD 样大鼠中由于多巴胺系统失调而更为明显，并且这种效应的神经生物学涉及 D3R 介导的大脑区域中控制冲动的 AMPA 受体 (Rs) 表面表达的增加。我提出三个具体目标来检验这些假设。将测试具有 6-羟基多巴胺诱导的背外侧纹状体损伤的大鼠和对照大鼠。 Napier 实验室已经证明，这些类似 PD 的老鼠获得并执行 ICSS 介导的概率贴现。在目标 1 中，我将评估低剂量阈上 PPX 对改善前肢迈步任务中运动缺陷的概率贴现效果 任务。我预测 PPX 将增强 PD 样大鼠的冒险行为，但不会增强对照大鼠的冒险行为，因为 PD 大脑状态的脆弱性增加。在目标 2 中，我将选择性 D3R 拮抗剂与 PPX 共同给药，并预测 PPX 诱导的冒险行为的发展和表达将被阻止。在目标 3 中，我将评估 D3R 介导的控制突触可塑性的细胞信号传导。我认为 D3R 激活可通过 Akt/GSK-3b 信号通路增强 AMPAR 向细胞表面的运输。我将使用 Napier 实验室正在进行的修改后的蛋白质印迹方案来评估 PPX 处理对 AMPAR 表面表达以及激活的 Akt 和 GSK-3b 信号传导水平的影响。我预测这种信号通路在 PD 样大鼠中的功效会增加。总之，这次培训机会将使我能够使用一种新颖的 ICD 临床前模型来开拓与 PPX 诱导的冒险行为相关的信号转导途径。因此，我的广泛培训不仅包括高度复杂的技术，还包括广泛应用的实验设计。这项令人兴奋的研究以及我的培训计划将为我未来从事神经病理学药物开发职业提供所有必要的技能，特别是那些运动功能疾病与心理健康失调同时发生的疾病。