PET imaging of Naltrexone Occupancy of Kappa Receptors in Heavy Drinkers

描述(由申请人提供)：该翻译项目的长期目标是优化阿片类拮抗剂纳曲酮(NTX)在治疗酒精依赖方面的使用，并为酒精饮料的新药物疗法确定新的受体靶点--NIAAA的优先事项。具体目标是召集专家，确定Kappa阿片受体(KOR)是否受到大量饮酒的影响，以及它们是否在调节NTX疗效的变异性方面发挥作用。知识差距：我们需要更多地了解酒精中毒、KOR以及NTX是如何减少酒精摄入量的。来自我们小组酒精饮酒范例(ADP)的有趣证据表明，酗酒和性别的家族史(FH)可能调节对NTX的反应。NTX减少了酒精中毒FH(FHP)阳性者的饮酒量，但似乎增加了FH(FHN)阴性者的饮酒量--这一差异在男性饮酒者中观察到，但在女性饮酒者中没有观察到。NTX与Mu、Delta和Kappa受体有不同程度的结合。之前的一项PET研究通过NTX测量了Mu和Delta站点的占有率(OCC)，但没有检查KOR，也没有与NTX疗效相关。另一项研究比较了酗酒者(HD)和健康对照组(HC)的基线Mu和Delta位点。由于缺乏特定的KOR示踪剂，KOR的PET成像一直是不可能的。创新：我们开发了一种选择性KOR示踪剂。目前的方案将首次使用这种示踪剂来(1)在基线时以高清成像可用KOR，(2)将基线时的HD与HC进行比较，以及(3)通过NTX、男性和女性、FHP和FHN HD来比较KOR的OCC。我们的初步PET证据表明，在HC中，基线KOR水平存在性别差异。这也提示FHP和FHN饮酒者在KOR的NTX OCC上存在差异，这可能与NTX引起的饮酒改变有关。我们的新数据表明，HD的KOR高于HC。这将与最近关于Mu遗址的发现背道而驰。我们的项目将首次研究在男性和女性重度饮酒者中，NTX引起的ADP饮酒变化与NTX引起的KOR OCC之间的关联。主要的假设是，在FHP和FHN HD中，NTX OCC将是不同的，这种差异将预测NTX的疗效。我们将使用一种新的示踪剂来阐明可能的影响 大量饮酒、NTX的行为、FH和性别相关的差异。这项工作将为未来对KOR/强啡肽系统的研究和寻找酒精中毒的药物疗法提供信息。

DESCRIPTION (provided by applicant): The long-term objectives of this translational project is to optimize the use of the opioid antagonist naltrexone (NTX) for treating alcohol dependence and to identify novel receptor targets for new pharmacotherapies for alcohol drinking - a priority of NIAAA. The specific objective is to bring together experts to determine if Kappa opioid receptors (KOR) are affected by heavy drinking and if they have a role in mediating variability in efficacy of NTX. Knowledge gap: We need to know more about alcoholism, KOR, and how NTX decreases alcohol intake. Intriguing evidence from our group with an alcohol drinking paradigm (ADP) suggests that family history (FH) of alcoholism and gender may mediate responses to NTX. NTX decreased drinking in those with a positive FH (FHP) of alcoholism but appeared to increase drinking in negative FH (FHN) - a difference observed in male but not female drinkers. NTX binds with varying degrees to Mu, Delta and Kappa receptors. A prior PET study measured occupancy (OCC) of Mu and Delta sites by NTX but did not examine KOR, nor correlate with NTX efficacy. Another study compared baseline Mu and Delta sites in heavy drinkers (HD) to healthy controls (HC). PET imaging of KOR has been impossible due to the lack of a specific KOR tracer. Innovation: We have developed a selective KOR tracer. The current proposal will be the first to use this tracer to (1) image available KOR in HD at baseline, (2) to compare HD at baseline to HC, and (3) to compare OCC of KOR by NTX, in male and female, FHP and FHN HD. Our preliminary PET evidence suggests gender differences in baseline KOR levels in HC. It also suggests that FHP and FHN drinkers differ in NTX OCC of KOR and this may be associated with NTX-induced changes in drinking. Our new data suggest that KOR are higher in HD than HC. This would be counter to the recent findings regarding the Mu site. Our project will be the first to examine the association of KOR OCC by NTX with NTX- induced changes in drinking in the ADP, in male and female heavy drinkers who are either FHP or FHN. The primary hypothesis is that NTX OCC will be different in FHP vs. FHN HD and that such differences will predict NTX efficacy. We will use a novel tracer to shed light on possible effects of heavy drinking, the actions of NTX, and FH and gender-related differences. The work will inform future studies into the KOR/dynorphin system and the search for pharmacotherapies for alcoholism.