The Nociceptin ORL1 System: Treatment Target for Relapse

描述（由申请方提供）：孤啡肽/孤啡肽FQ（N/oFQ）是一种最近分离的神经肽，是阿片受体样1（ORL 1）受体的内源性配体。支持该应用的初步数据表明，ORL 1激动剂产生功能性抗阿片类药物以及功能性抗CRF作用。考虑到已知阿片类药物和CRF传递的拮抗作用可阻断复发的两个重要风险因素-压力和酒精线索暴露-在复发动物模型中的各自作用，ORL 1激动剂的这种双重作用将N/ORL-ORL 1系统确定为“抗复发”药物的非常有希望的靶点。因此，本提案旨在系统地研究N/ORL-ORL 1系统在乙醇寻求行为调节中的作用，有两个相关的主要目标。第一个目标（将在具体目标1中进行）是通过研究新的、选择性非肽ORL 1受体激动剂Ro 64-6198对由应激和乙醇线索诱导的乙醇寻求恢复的作用，并通过将该药剂的作用与CRF拮抗剂，苯并二氮杂卓，和阿片拮抗剂（即，具有确定的抗应激、抗焦虑或抗渴望作用的药剂）。第二个目标（将在具体目标2 - 4中进行）是在神经解剖学、神经回路和神经化学水平上阐明N/ORL-ORL 1系统调节应激和酒精线索诱导的乙醇寻求的神经生物学基础。所有具体目标将包括一组额外的目标，即深入了解N/ORL-ORL 1系统的神经适应性变化，这可能是慢性乙醇暴露后复发脆弱性发展的基础，并深入了解该系统的先天失调，这可能会对压力和酒精线索暴露的激励作用产生更高的易感性。为此，将在乙醇历史或遗传决定的乙醇偏好不同的大鼠中生成数据并进行比较，因此，推测参与乙醇寻求行为的动机程度不同。这些受试者群体包括（1）具有每日有限获取乙醇自我给药史的遗传异质性Wistar大鼠，（2）具有先前乙醇依赖史但在戒断后3 - 4周进行测试的Wistar大鼠（即，在“长期戒断”阶段期间），和（3）遗传选择的Marchigian酒精偏好（msP）大鼠，一种已经被提出代表遗传易复发性的动物模型的大鼠系。在系统水平上的乙醇-N/OFQ相互作用的新信息，以及与其他神经化学系统在调节乙醇寻求行为中的相互作用，预计将有助于开发针对N/OFQ-ORL 1受体系统或相关药理学靶点的“抗复发”治疗。

DESCRIPTION (provided by applicant): Nociceptin/orphanin FQ (N/oFQ), a recently isolated neuropeptide is the endogenous ligand of the opioid receptor-like1 (ORL1) receptor. Preliminary data supporting this application suggest that ORL1 agonists produce functional anti-opioid as well as functional anti-CRF effects. Considering that antagonism of opioid and CRF transmission is known to block the respective effects of two important risk factors for relapse -- stress and alcohol cue exposure - in animal models of relapse, this dual action of ORL1 agonists identifies the N/oFQ-ORL1 system as a highly promising target for "anti-relapse" medications. This present proposal was, therefore, developed to systematically investigate the role of the N/oFQ-ORL1 system in the regulation of ethanol-seeking behavior, with two related major goals. The first goal (to be pursued in Specific Aim 1) is to establish that the ORL1 receptor represents an effective treatment target for relapse prevention by studying the effects of a novel, selective non-peptide ORL1 receptor agonist Ro 64-6198 on reinstatement of ethanol-seeking induced by stress and ethanol cues and by comparing the effects of this agent to those of a CRF antagonist, a benzodiazepine, and an opiate antagonist (i.e., agents with established anti-stress, anxiolytic, or anti-craving action). The second goal (to be pursued in Specific Aims 2 - 4) is to elucidate the neurobiological basis for the regulation of stress and alcohol cue-induced ethanol-seeking by the N/oFQ-ORL1 system at the neuroanatomical, neurocircuitry, and neurochemical level. All Specific Aims will include an additional set of objectives which is to provide insight into neuroadaptive changes in the N/oFQ-ORL1 system that may underlie the development of vulnerability to relapse following chronic ethanol exposure, and into innate dysregulations of this systems that may convey heightened susceptibility to the motivating effects of stress and alcohol cue exposure. For this purpose, data will be generated in and compared among rats differing in ethanol history or genetically-determined ethanol preference and, thus, presumably in the degree of motivation to engage in ethanol-seeking behavior. These subject populations include (1) genetically heterogeneous Wistar rats with a history of daily limited-access ethanol self-administration, (2) Wistar rats with a history of prior ethanol dependence, but tested 3 - 4 weeks following withdrawal (i.e., during the "protracted withdrawal" phase), and (3) genetically selected Marchigian Alcohol Preferring (msP) rats, a line of rats that has been proposed to represent an animal model of genetic vulnerability to relapse. Novel information on ethanoI-N/oFQ interactions at the systems level, and interactions with other neurochemical systems in regulating ethanol-seeking behavior to be generated by these studies is expected to aid in developing "anti-relapse" treatments aimed at the N/oFQ-ORL1 receptor system or related pharmacological targets.