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。

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.