A novel rodent model of dopamine agonist-induced impulsive control disorders

描述（由申请人提供）：多巴胺（DA）激动剂，普拉克索（PPX; Mirapex（R））和罗匹尼罗（ROP; RNP（R））是FDA批准用于治疗帕金森病（PD）和不宁腿综合征的运动功能障碍。接受DA受体激动剂治疗的这些患者中有相当一部分发生冲动控制障碍（ICD），如赌博障碍、强迫性行为、强迫性购买和暴食。有强有力的证据表明ICD与DA激动剂治疗相关;缺乏ICD的临床前模型来验证这一假设。ICD的一个共同方面是倾向于选择立即可用的奖励，而不是直到后来才能获得的较大奖励（即，立即选择5美元的奖励，而不是下周选择50美元）。这种冲动的选择倾向可以在啮齿动物中使用延迟折扣任务来测量。在这项任务中，食物通常是食物的形式，然而，由于驱动ICD的奖励的可变性（例如，金钱、性、购物以及食物），这个选项不是最佳的。我们提出了一种新的方法，使用颅内自我刺激（ICSS）直接靶向神经回路，这是所有驱动ICD的奖励所共有的。我们认为这是一种大大改进的ICD建模方法。因此，当前资助申请的目的是使用ICSS作为正向贴现器的延迟贴现范例开发ICD的啮齿动物模型。一旦开发出来，这种模型将允许对ICD的神经生物学和药理学进行研究。因此，我们的中心假设是：（1）用于治疗PD和其他神经系统疾病的DA激动剂将增加PD样大鼠和对照大鼠的冲动选择，（2）DA D3受体（D3 Rs）是DA激动剂诱导冲动的基础。我们提出了两个具体目标来检验这些假设。在目的1中，我们将实施ICSS介导的延迟折扣，以在PD和非PD对照大鼠的良好建立的6-OHDA处理的大鼠模型中建立冲动选择的基础水平。我们假设PPX和ROP治疗将促进两组大鼠的冲动选择。在目标2中，我们将测试这样的假设：高选择性D3 R拮抗剂将阻止PD样大鼠和对照大鼠中PPX和ROP诱导的冲动选择的发展和表达。PPX和ROP激活D2 R家族中的所有受体;然而，两者对D3 R亚型的亲和力略高，D3 R亚型在大脑的奖励区域中高度表达。因此，我们预期目标2的结局将验证D3 R亚型对ICD至关重要。总之，这两个特定目标中提出的工作预计将在PD样大鼠和对照大鼠中产生ICD的创新模型，并确定D3 R在该现象中的作用。这些结果有望为转化研究奠定基础，以验证目前关于DA激动剂诱导冲动的理论，并可能导致PD和非PD疾病症状的更好治疗，同时减少ICD等不良反应的负担。此外，我们预测该模型将提供一种全新的手段，用于快速筛选开发中的化合物作为CNS疾病的治疗药物，以确定化合物诱导ICD的潜力。 公共卫生相关性：这项拟议的研究与公共卫生有关，因为它将开发一种新的范式，评估冲动控制障碍的神经生物学基础，并确定为什么用于帕金森病和其他神经病理学的一些治疗方法会导致这些疾病。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。因此，拟议的研究是相关的NIH的使命的一部分，涉及到对冲动控制障碍的性质的基础知识的追求。

DESCRIPTION (provided by applicant): Dopamine (DA) gonists, pramipexole (PPX; Mirapex(R)) and ropinirole (ROP; Requip(R)) are FDA-approved for the treatment of motor dysfunction in Parkinson's disease (PD) and restless leg syndrome. A significant subset of these patients treated with DA agonists develop impulse control disorders (ICDs) such as gambling disorders, compulsive sexual behavior, compulsive buying, and binge-eating. There is strong evidence that ICDs are associated with DA agonist therapy; lacking are preclinical models of ICDs to test this assumption. One common aspect of ICDs is the tendency to choose immediately available rewards over larger rewards that cannot be obtained until later (i.e., choosing a $5 reward immediately vs. $50 next week). This impulsive choice tendency can be measured in rodents using a delayed discounting task. In this task, reinforcers are typically in the form of food, however, due to the variability of rewards that drive ICDs (e.g., money, sex, shopping, as well as food) this option is not optimal. We pose a new approach which uses intracranial self- stimulation (ICSS) to directly target the neurocircuitry that is common to all rewards that drive ICDs. We contend this is a far improved means to model ICDs. Thus, the objective of the current grant application is to develop a rodent model of ICDs using a delayed discounting paradigm with ICSS as a positive reinforcer. Once developed, such a model will allow investigations into the neurobiology and pharmacology of ICDs. Accordingly, our central hypotheses are that (1) DA agonists used to treat PD and other neurological disorders will increase impulsive choice in PD-like and control rats, and (2) DA D3 receptors (D3Rs) underlie DA agonist-induced impulsivity. We propose two Specific Aims to test these hypotheses. In Aim 1, we will implement ICSS-mediated delayed discounting to establish basal levels of impulsive choice in a well- established 6-OHDA-treated rat model of PD and non-PD control rats. We hypothesize that treatment with PPX and ROP will promote impulsive choice in both groups of rats. In Aim 2, we will test the hypothesis that highly selective D3R antagonists will block development and expression of PPX- and ROP-induced impulsive choice in both PD-like and control rats. PPX and ROP activate all receptors in the D2R family; however both have slightly higher affinity for the D3R subtype, which is highly expressed in reward regions of the brain. Thus, we expect Aim 2 outcomes to verify that the D3R subtype is critical for ICDs. In sum, the work proposed in these two Specific Aims are expected to produce an innovative model of ICDs in PD-like and control rats, and to establish a role for D3Rs in this phenomenon. Such results are expected to set the stage for translational research to validate current theories regarding DA agonist-induced impulsivity and potentially lead to better treatments for symptoms in PD and non-PD disorders, while reducing the burden of untoward effects such as ICDs. Moreover, we predict this model will provide a completely new means to rapidly screen compounds under development as therapeutics for CNS disorders for potential of the compound to induced ICDs. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will develop a new paradigm that will assess the neurobiological underpinnings of impulse control disorders and determine why some treatments used for Parkinson's disease, and other neuropathologies, result in these disorders. Understanding the neurobiology of impulse control disorders should lead to better treatments that are devoid of these devastating side effects. Thus, the proposed research is relevant to the part of NIH's mission that pertains to the pursuit of fundamental knowledge about the nature of impulse control disorders.