NOCICEPTIN RECEPTORS IN REWARD CIRCUITS AND BEHAVIOR

摘要：阿片受体已成为治疗疼痛和相关疾病的靶点已有数千人 很多年了。已经鉴定了三种阿片受体，第四种阿片受体称为伤害素 (NOPR)或阿片受体样蛋白-1是该家族的最新成员。最近的证据表明， 阿片受体可能是成瘾、焦虑和抑郁的新靶点。此外，有报道称 提示NOPR-伤害素系统参与可卡因奖赏行为。然而，在什么地方 大脑NOPR受体调节这些行为，NOPR是如何被调控的，以及它是如何被信号传递的 已定义。为了更好地理解这一系统在行为中的作用，我们提出了两个目标：1)我们将 确定NOPR和NOPR信号突变体在特定细胞和多巴胺能神经回路中的作用 使用有针对性的病毒救援策略和行为模型来控制可卡因偏好行为。在这里我们 将使用野生型病毒介导的细胞类型在小鼠身上进行特定的“敲入”功能获得实验 和突变受体，以确定NOPR受体如何在控制可卡因的多巴胺能回路中发挥作用 在体内的偏好性。2)在目标2中，我们将结合使用小鼠遗传学、解剖学技术和 TD番茄报告小鼠，和光遗传学方法剖析含有伤害素的神经元在 可卡因地点偏好、奖励和厌恶行为。总而言之，这个项目和实验 为研究伤害素-NOPR系统在药物中的作用提供了新的重要信息 滥用行为。

Abstract: Opioid receptors have been targeted for the treatment of pain and related conditions for thousands of years. Three opioid receptors have been characterized, with a fourth opioid receptor called nociceptin (NOPR) or opioid-receptor like-1 being the newest member of the family. Recent evidence has shown that opioid receptors are potentially novel targets for addiction, anxiety, and depression. Furthermore, reports suggest that the NOPR - nociceptin system is involved in cocaine reward behavior. However, where in the brain NOPR receptors modulate these behaviors, how NOPR is regulated, and how it signals has not been defined. In order to better understand the role of this system in behavior we propose 2 aims: 1) We will determine how NOPR and NOPR -signaling mutants function in specific cells and dopaminergic neural circuits to control cocaine preference behavior using targeted viral rescue strategies, and behavioral models. Here we will employ viral-mediated cell type specific "knock-in" gain-of-function experiments in mice, using wild-type and mutant receptors to determine how NOPR receptors function in dopaminergergic circuits to control cocaine preference in vivo. 2) In aim 2 we will use a combination of mouse genetics, anatomical techniques with tDtomato-reporter mice, and optogenetic approaches to dissect the role of nociceptin containing neurons on cocaine place preference, reward, and aversion behavior. Together, this project and the experiments described could provide novel and important information about nociceptin-NOPR system function in drug abuse behaviors.