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

描述(申请人提供)：这份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)的翻译研究项目 帕金森氏病(PD)。普拉克索(PPX)是一种多巴胺(DA)D3受体(D3R)偏爱激动剂，用于治疗帕金森病患者的运动功能障碍。接受治疗的患者中有相当一部分(例如，13.6%1)会患上ICDS，即病态赌博、性欲亢进、强迫购物和暴饮暴食等行为成瘾。我们的实验室在大鼠身上建立了一种新的概率贴现任务，通过使用颅内自我刺激(ICSS)作为积极增强剂来衡量“冒险行为”。使用这个模型，我计划确定D3R在PPX诱导的折扣中的作用。此后，我计划确定D3R介导的效应是否涉及已知的调节学习和药物/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导致冒险行为增加，由于多巴胺系统调节失调，这可能在类似帕金森病的大鼠中更加明显，这种效应的神经生物学涉及D3R介导的AMPA受体(Rs)在控制冲动的大脑区域的表面表达增加。我提出了三个具体目标来检验这些假设。6-羟基多巴胺诱导的大鼠背外侧纹状体损伤和对照组将被测试。纳皮尔实验室已经证明，这些类似帕金森病的大鼠获得并执行ICSS介导的概率贴现。在目标1中，我将在概率折扣中评估小剂量的PPX对改善前肢步态任务中运动缺陷的效果 任务。我的预测是，PPX将提高帕金森病样大鼠的冒险行为，但在对照组大鼠中不会，因为帕金森病患者大脑状态的脆弱性增加。在目标2中，我将联合使用选择性D3R拮抗剂和PPX，并预测PPX诱导的风险承担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。我认为D3R的激活通过Akt/GSK-3b信号通路促进AMPAR向细胞表面的转运。我将使用纳皮尔实验室正在进行的改进的Western印迹方法来评估PPX处理对AMPAR表面表达的影响，以及激活Akt和GSK-3b信号的水平。我预测这一信号通路在类帕金森病大鼠中的有效性将会增加。总而言之，这次培训机会将使我能够使用一种新的ICD临床前模型来开创与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非常复杂的技术，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，将为我未来在神经病理药物开发方面的职业生涯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并存的疾病。 公共卫生相关性：这项拟议的研究与公共健康相关，并推进了NIH的使命，因为它与追求与帕金森氏症共同发生的冲动控制障碍的性质有关的基本知识有关。了解冲动控制障碍的神经生物学应该会带来更好的治疗方法，而不会产生这些毁灭性的副作用。拟议研究的完成将推动PD和ICD领域的发展，并为这些行为的发展提供一种新的机制。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health and advances NIH's mission because it pertains to the pursuit of fundamental knowledge about the nature of impulse control disorders co-occurring with Parkinson's disease. Understanding the neurobiology of impulse control disorders should lead to better treatments that are devoid of these devastating side effects. Completion of the proposed studies will move the field vertically by furthering the field in both PD and ICDs and providing a novel mechanism underlying the development of these behaviors.