The nociceptin ORL1 System: Treatment Target for Relapse

描述（由申请人提供）：该研究项目将通过竞争更新继续进行，涉及脑伤害肽/孤啡肽FQ （N/OFQ）阿片类神经肽系统在酒精成瘾中的作用。在上一个资助期内的研究是专门针对N/OFQ系统对酒精滥用的治疗目标潜力，重点是预防复发。拟议的研究与这项工作是持续的，并有两个总体目标。第一个是关于N/OFQ的行为效应，通过(a)检查N/OFQ对乙醇（乙醇）依赖史大鼠的几种神经行为效应（即存在神经适应性变化的状态，包括N/OFQ系统的适应，这些变化将“负面影响”作为动机维度添加到乙醇寻求和奖励中，并可能修改N/OFQ系统激活的行为效应）；(b)通过建立N/OFQ重复给药的效果，以确定这种治疗是否如基于初步数据的假设那样增强了N/OFQ激活的“治疗”效果，或者，或者，导致对肽的特定行为效应的耐受性，以及(c)通过比较N/OFQ在不同系的大鼠、Wistar和Marchigian撒丁岛酒精偏好大鼠（msP）之间的行为效应。后者携带先天的N/OFQ系统失调。第二个目的是阐明EtOH诱导的（依赖史）或先天（msP大鼠）N/OFQ功能改变与EtOH寻求或奖励之间关系的神经生物学基础，并确定重复的N/OFQ给药是否会逆转这些N/OFQ功能的改变。这些目标将通过一套四个具体目标来实现。其中三项将重点关注急性和重复N/OFQ治疗对与乙醇依赖史相关的行为后果的影响。在SPECIFIC AIM 1中，将在Wistar和有与无EtOH依赖史的msP大鼠中建立急性和重复N/OFQ治疗对EtOH自我给药的影响。在SPECIFIC AIM 2中，将利用动物复发模型来确定N/OFQ对急性足部休克应激或与etoh相关的情境刺激诱导的etoh寻求的影响。在SPECIFIC AIM 3中，N/OFQ对焦虑增加和压力挑战敏感性的影响将在两种焦虑行为模型中进行检验。最后，SPECIFIC AIM 4的目标是确定与msP大鼠相比，EtOH依赖史如何改变Wistar大鼠中N/OFQ系统的功能，确定重复使用N/OFQ治疗Wistar大鼠与msP大鼠中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。这些研究将在多个层面进行分析，包括N/OFQ肽和NOP受体mRNA的原位杂交表达，NOP受体放射自显影，以及使用[35S]GTP3S结合测量NOP神经传递的功能状态。制定研究计划的目的是促进对N/OFQ系统的治疗目标潜力的理解，特别是对酒精依赖的生物学基础的理解。

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