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

描述（由申请人提供）：多巴胺（DA）拮抗剂，普拉克索（PPX; Mirapex(R)）和罗匹尼罗（ropininirole; Requip(R)）是fda批准用于治疗帕金森病（PD）和不宁腿综合征运动功能障碍的药物。在这些接受DA激动剂治疗的患者中，有相当一部分人出现了冲动控制障碍（ICDs），如赌博障碍、强迫性性行为、强迫性购物和暴饮暴食。有强有力的证据表明，icd与DA激动剂治疗有关；缺乏icd的临床前模型来验证这一假设。icd的一个常见方面是，玩家倾向于选择立即可用的奖励，而不是稍后才能获得的更大奖励（即选择立即获得的5美元奖励vs.下周获得的50美元奖励）。这种冲动选择倾向可以在啮齿类动物中使用延迟折扣任务来测量。在这个任务中，强化物通常以食物的形式出现，然而，由于驱动icd的奖励的可变性（例如，金钱、性、购物和食物），这种选择并不是最优的。我们提出了一种新的方法，即使用颅内自我刺激（ICSS）直接靶向所有驱动ICDs的奖励共同的神经回路。我们认为这是对icd建模的一种大大改进的方法。因此，当前拨款申请的目标是使用延迟贴现范式开发ICDs的啮齿动物模型，ICSS作为正强化物。一旦开发出来，这样的模型将允许对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激动剂会增加PD样鼠和对照大鼠的冲动选择，(2)DA D3受体（D3Rs）是DA激动剂诱导冲动的基础。我们提出两个具体目标来检验这些假设。在第1项研究中，我们将采用icss介导的延迟折现，在已建立的6-羟色胺治疗的帕金森大鼠模型和非帕金森对照大鼠中建立冲动性选择的基础水平。我们假设PPX和ROP治疗会促进两组大鼠的冲动选择。在Aim 2中，我们将验证高选择性D3R拮抗剂将阻断pd样和对照大鼠PPX和rop诱导的冲动选择的发育和表达的假设。PPX和ROP激活D2R家族的所有受体；然而，两者对D3R亚型的亲和力略高，D3R亚型在大脑的奖励区域高度表达。因此，我们期望Aim 2的结果验证D3R亚型对icd至关重要。总之，这两个特定目标中提出的工作有望在pd样和对照大鼠中建立一种创新的icd模型，并确定D3Rs在这一现象中的作用。这些结果有望为转化研究奠定基础，以验证目前有关DA激动剂诱导冲动的理论，并有可能为PD和非PD疾病的症状提供更好的治疗方法，同时减少诸如ICDs等不良影响的负担。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用于治疗中枢神经系统疾病的化合物，以了解该化合物诱导icd的潜力。

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.