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; Requip(R)) 已获得 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。这些接受 DA 激动剂治疗的患者中有很大一部分出现了冲动控制障碍 (ICD)，例如赌博障碍、强迫性行为、强迫性购买和暴饮暴食。有强有力的证据表明 ICD 与 DA 激动剂治疗相关；缺乏 ICD 的临床前模型来检验这一假设。 ICD 的一个共同点是倾向于选择立即可用的奖励，而不是稍后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 美元的奖励）。可以使用延迟贴现任务在啮齿动物中测量这种冲动选择倾向。在这项任务中，强化物通常以食物的形式存在，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），这种选择并不是最佳选择。我们提出了一种新方法，使用颅内自刺激（ICSS）直接针对驱动 ICD 的所有奖励所共有的神经回路。我们认为这是一种大大改进的 ICD 建模方法。因此，当前拨款申请的目标是使用延迟贴现范式和 ICSS 作为正强化物来开发 ICD 啮齿动物模型。一旦开发出来，这样的模型将有助于研究 ICD 的神经生物学和药理学。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 激动剂会增加 PD 样大鼠和对照大鼠的冲动选择，(2) DA D3 受体 (D3R) 是 DA 激动剂诱导的冲动的基础。我们提出两个具体目标来检验这些假设。在目标 1 中，我们将实施 ICSS 介导的延迟贴现，以在完善的 6-OHDA 治疗的 PD 和非 PD 对照大鼠模型中建立冲动选择的基础水平。我们假设 PPX 和 ROP 治疗会促进两组大鼠的冲动选择。在目标 2 中，我们将测试以下假设：高度选择性的 D3R 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育和表达。 PPX 和 ROP 激活 D2R 家族中的所有受体；然而，两者对 D3R 亚型的亲和力稍高，D3R 亚型在大脑的奖励区域中高度表达。因此，我们预计目标 2 结果将验证 D3R 亚型对于 ICD 至关重要。总之，这两个具体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 D3R 在这种现象中的作用。这些结果预计将为转化研究奠定基础，以验证当前有关 DA 激动剂诱发冲动的理论，并有可能为 PD 和非 PD 疾病的症状提供更好的治疗方法，同时减轻 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方法来快速筛选正在开发的化合物，作为 CNS 疾病的治疗药物，以确定该化合物诱导 ICD 的潜力。 公共健康相关性：拟议的研究与公共健康相关，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，并确定为什么某些用于帕金森病和其他神经病理学的治疗会导致这些疾病。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，避免这些破坏性的副作用。因此，拟议的研究与 NIH 使命的一部分相关，即追求有关冲动控制障碍本质的基础知识。

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.