The nociceptin ORL1 System: Treatment Target for Relapse

描述（由申请人提供）：通过本次竞争性更新继续进行的研究计划涉及脑伤害感受素/阿片肽在酒精成瘾中FQ（N/OFQ）阿片神经肽系统中的作用。上一个资助期的研究致力于N/OFQ系统对酒精滥用的治疗靶点潜力，重点是预防复发。拟议的研究是这项工作的延续，有两个总体目标。第一个是关于N/OFQ的行为效应，通过（a）在具有乙醇（EtOH）依赖史的大鼠中检查N/OFQ对乙醇的几种神经行为效应的作用（即，存在神经适应性变化的状态，包括N/OFQ系统中的适应，其将“负面影响”作为激励维度添加到EtOH寻求和奖励中，并且可以修改N/OFQ系统激活的行为效应），（B）通过建立重复N/OFQ给药的作用以确定该治疗是否增强N/OFQ的“治疗”功效，根据初步数据假设的OFQ激活，或者，可替代地，导致对肽的特定行为效应的耐受性，和（c）通过比较N/OFQ在EtOH偏好不同的大鼠品系中的行为效应，Wistar和Marchigian Sardinian酒精偏好大鼠（msP），后者携带N/OFQ系统的先天失调。第二个目的是阐明EtOH诱导的（依赖史）或先天性（msP大鼠）N/OFQ功能改变与EtOH寻求或奖励之间的关联的神经生物学基础，以及确定重复N/OFQ给药是否逆转N/OFQ功能的这些改变。这些目标将通过四个具体目标来实现。其中三个将集中在急性和重复N/OFQ治疗与酒精依赖史相关的行为后果的影响。在特定目的1中，将在Wistar和msP大鼠中确定急性和重复N/OFQ处理对EtOH自我给药的影响，其中有与没有EtOH依赖史。在特定目的2中，将利用复发的动物模型来确定N/OFQ对急性足电击应激或EtOH相关背景刺激诱导的EtOH寻求的影响。在具体目标3中，将在两种焦虑行为模型中检查N/OFQ对增加的焦虑和对压力挑战的敏感性的影响。最后，具体目标4的目标是确定与msP大鼠相比，EtOH依赖史如何改变Wistar大鼠N/OFQ系统的功能，以确定Wistar大鼠与msP大鼠重复N/OFQ治疗产生的N/OFQ-NOP神经传递的变化，从而阐明N/OFQ对EtOH摄入、EtOH寻求、焦虑和应激反应的抑制作用的机制。这些研究将在几个分析水平上进行，包括通过原位杂交、NOP受体放射自显影和使用[35 S] GTP 3S结合测量NOP神经传递的功能状态来分析N/OFQ肽和NOP受体mRNA表达。该研究计划的目的是促进对N/OFQ系统的治疗靶点潜力的理解，特别是酒精依赖的生物学基础。 公共卫生相关性：这项竞争性更新申请中提出的研究旨在继续阐明FQ（N/OFQ）阿片类神经肽系统中脑伤害感受素/阿片肽在酒精滥用和成瘾中的作用，重点是该系统的治疗靶点潜力。这项研究有望促进对酒精依赖生物学基础的理解，并揭示酒精滥用和酒精中毒的新治疗靶点。

DESCRIPTION (provided by applicant): The research program to be continued through this competing renewal is concerned with the role of the brain nociceptin/orphanin FQ (N/OFQ) opioid neuropeptide system in alcohol addiction. Studies during the previous funding period were dedicated to the treatment target potential of the N/OFQ system for alcohol abuse with emphasis on relapse prevention. The proposed studies are continuous with this work and have two overarching goals. The first is concerned with the behavioral effects of N/OFQ by (a) examining N/OFQ actions on several neurobehavioral effects of ethanol in rats with a history of ethanol (EtOH) dependence (i.e., a state in which neuroadaptive changes exist, including adaptations in the N/OFQ system, that add "negative affect" as a motivational dimension to EtOH-seeking and reward, and that may modify the behavioral effects of N/OFQ system activation), (b) by establishing the effects of repeated N/OFQ administration to determine whether this treatment enhances the "therapeutic" efficacy of N/OFQ activation as hypothesized on the basis of the preliminary data or, alternatively, results in tolerance to specific behavioral effects of the peptide, and (c) by comparing the behavioral effects of N/OFQ across lines of rats differing in EtOH preference, Wistar and Marchigian Sardinian Alcohol Preferring rats (msP), the latter carrying an innate dysregulation of the N/OFQ system. The second objective is to elucidate the neurobiological basis of the association between EtOH- induced (history of dependence) or innate (msP rats) alterations in N/OFQ function and EtOH-seeking or reward, as well as to determine whether repeated N/OFQ administration reverses these alterations in N/OFQ function. These objectives will be accomplished in a set of four Specific Aims. Three of these will focus on the effects of acute and repeated N/OFQ treatment on behavioral consequences associated with a history of ethanol dependence. In SPECIFIC AIM 1 the effects of acute and repeated N/OFQ treatment on EtOH self- administration will be established in Wistar and in msP rats with vs. without a history of EtOH dependence. In SPECIFIC AIM 2, animal models of relapse will be utilized to establish the effects of N/OFQ on EtOH-seeking induced by acute footshock stress or EtOH-associated contextual stimuli. In SPECIFIC AIM 3, the effects of N/OFQ on increased anxiety and sensitivity to stress challenges will be examined in two behavioral models of anxiety. Finally, the goal of SPECIFIC AIM 4 is to determine how a history of EtOH dependence alters the function of the N/OFQ system in Wistar compared to msP rats, to identify changes in N/OFQ-NOP neurotransmission produced by repeated N/OFQ treatment in Wistar vs. msP rats, and thereby to shed light on the mechanisms responsible for the inhibitory actions of N/OFQ on EtOH intake, EtOH-seeking, anxiety, and stress reactivity. These studies will be conducted at several levels of analysis including N/OFQ peptide and NOP receptor mRNA expression by in situ hybridization, NOP receptor autoradiography, and measures of the functional status of NOP neurotransmission using [35S]GTP3S binding. The research plan has been developed with the objective of advancing understanding of the treatment target potential of the N/OFQ system, in particular, and of the biological basis of alcohol dependence, in general. PUBLIC HEALTH RELEVANCE: The research proposed in this competing renewal application seeks to continue to elucidate the role of the brain nociceptin/orphanin FQ (N/OFQ) opioid neuropeptide system in alcohol abuse and addiction with emphasis on the treatment target potential of this system. This research is expected to advance understanding the biological basis of alcohol dependence, and to reveal novel treatment targets for alcohol abuse and alcoholism