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

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（D3 R）偏好激动剂，用于治疗PD运动功能障碍。治疗患者的重要子集（例如，13.6%1）开发ICD，即，行为成瘾，如病态赌博，性欲亢进，强迫性购物和暴食。我们的实验室在大鼠中建立了一种新的概率折扣任务，该任务通过使用颅内自我刺激（ICSS）作为阳性标记来测量“冒险”。使用这个模型，我计划确定D3 R在PPX诱导的折扣中的作用。此后，我计划确定D3 R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，运输的药物能受体AMPA。因此，我的总体假设是，PPX激活D3 R导致冒险行为增加，这可能在PD样大鼠中由于多巴胺系统失调而更加明显，并且这种效应的神经生物学涉及D3 R介导的AMPA受体（Rs）在控制冲动的大脑区域中的表面表达增加。我提出了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。纳皮耶实验室已经证明，这些PD样大鼠获得并执行ICSS介导的概率折扣。目的1：评价阈上低剂量PPX对概率折扣法前肢跨步运动障碍的改善作用 任务我的预测是，PPX将增强PD样大鼠的冒险行为，但由于PD大脑状态的脆弱性增加，在对照大鼠中不会。在目标2中，我将与PPX共同给予选择性D3 R拮抗剂，并预测PPX诱导的冒险行为的发展和表达将被阻断。在目标3中，我将评估D3 R介导的控制突触可塑性的细胞信号传导。我建议，D3 R激活增强AMPAR贩运到细胞表面通过Akt/GSK-3b信号通路。我将使用纳皮耶实验室正在进行的改良蛋白质印迹法评估PPX处理对AMPAR表面表达的影响，以及激活的Akt和GSK-3b信号传导水平。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新型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，我广泛的培训不仅包括高度复杂的技术，而且还包括广泛应用的实验设计。这项令人兴奋的研究，沿着我的培训计划，将为我未来的神经病理学药物开发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精神健康失调并存的疾病。 公共卫生相关性：拟议的研究与公共卫生有关，并推进了NIH的使命，因为它涉及对与帕金森病共同发生的冲动控制障碍性质的基础知识的追求。了解冲动控制障碍的神经生物学应该会导致更好的治疗方法，而这些治疗方法没有这些毁灭性的副作用。完成拟议的研究将垂直移动该领域，进一步在PD和ICD领域，并提供一个新的机制，这些行为的发展。

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.