NOP Receptors in nonhuman primate models of AUD

项目摘要。 酒精使用障碍（AUD）是一个昂贵的公共卫生问题，缺乏广泛有效的药物。 这项研究的科学前提是，FQ肽中伤害感受素/神经递质的脑受体 (NOP)是新药的有希望的靶点，但在复杂的非人类灵长类动物中的转化研究 (NHP)需要模型为药物开发和临床试验提供信息和指导。这个前提是基于 来自啮齿动物模型的令人鼓舞的数据和来自我们的NHP实验室的积极初步数据， 丁丙诺啡及其衍生物BU 08028被称为“双功能”MOP/NOP激动剂，因为它刺激 NOP和μ阿片肽（MOP）受体。拟议的研究结合了联合收割机， 慢性乙醇（EtOH）饮用的临床相关NHP模型，新型NOP和MOP/NOP作用药物， 使用正电子发射的药物治疗评估和非侵入性脑成像的平移方法 断层扫描（PET成像）。使用既定程序诱导雄性和雌性动物饮用EtOH后， 恒河猴将可以自由接触乙醇;也将对接受食物颗粒的反应进行监测， 潜在副作用指数。具体目标1将确定丁丙诺啡及其衍生物的作用 BU 08028，与选择性刺激或阻断MOP或NOP受体的药物组合。结果将 揭示MOP和NOP受体刺激对双功能激动剂的能力的相对贡献， 减少EtOH饮用，表明药物的理想药理学特征。下一个（目标2）， 具有所需特征的化合物将选自通过Co- 调查员斯蒂芬·赫斯班德博士候选人将在几个月内每天接受管理， 中度和重度饮酒（每天分别为6或22小时）将使用翻译 P.I.开发的方法我们希望能找到一种化合物， 乙醇饮用不会改变食物维持反应或产生不良影响。目标3包括 使用新型放射性示踪剂[11 C]NOP-1A的PET成像研究，与目标1和2平行。这些研究 将表征（1）基础NOP受体可用性对EtOH初始敏感性的影响，（2） （3）有效治疗对NOP受体的影响 可用性，（4）戒除EtOH期间NOP受体可用性的恢复程度， （5）在所有这些措施中存在性别差异。总之，这些研究的结果将提供新的， 翻译数据支持开发MOP/NOP和NOP选择性激动剂的可行性和有效性 作为新型AUD药物疗法，使用转化的、临床相关的NHP模型。

PROJECT SUMMARY. Alcohol use disorder (AUD) persists as a costly public health problem that lacks widely effective medications. The scientific premise of the proposed research is that brain receptors for the nociceptin/orphanin FQ peptide (NOP) are promising targets for new medications, but translational studies in sophisticated nonhuman primate (NHP) models are needed to inform and direct drug development and clinical testing. This premise is based on encouraging data from rodent models and positive preliminary data from our NHP laboratory using buprenorphine and its derivative BU08028, termed a “bifunctional” MOP/NOP agonist because it stimulates both NOP and mu opioid peptide (MOP) receptors. The proposed studies combine a well-characterized, clinically relevant NHP model of chronic ethanol (EtOH) drinking, novel NOP- and MOP/NOP-acting drugs, a translational method of pharmacotherapy assessment and noninvasive brain imaging using positron emission tomography (PET imaging). After being induced to drink EtOH using established procedures, male and female rhesus monkeys will have free access to EtOH; responding to receive food pellets will also be monitored as an index of potential side effects. Specific Aim 1 will determine the effects of buprenorphine and its derivative BU08028, in combination with drugs that selectively stimulate or block MOP or NOP receptors. The results will reveal the relative contribution of MOP and NOP receptor stimulation to the ability of bifunctional agonists to decrease EtOH drinking, indicating the ideal pharmacological profile for a medication. Next (Aim 2), drugs that possess the desired profile will be selected from among a catalog of novel compounds synthesized by Co- Investigator Dr. Stephen Husbands. Candidates will be administered daily for several months and effects on moderate and heavy drinking (6 or 22 hours per day, respectively) will be determined using a translational approach developed by the P.I. We expect to identify a compound that produces prolonged suppression of EtOH drinking without altering food-maintained responding or producing adverse effects. Aim 3 consists of PET imaging studies using the novel radiotracer [11C]NOP-1A that run parallel to Aims 1 and 2. These studies will characterize (1) the influence of basal NOP receptor availability on initial sensitivity to EtOH, (2) the effects of long-term EtOH drinking on NOP receptors, (3) the effects of efficacious treatments on NOP receptor availability, (4) the extent of recovery of NOP receptor availability during abstinence from EtOH and, importantly, (5) sex differences in all these measures. Together, the results of these studies will provide novel, translational data to support the feasibility and efficacy of developing MOP/NOP and NOP-selective agonists as novel AUD pharmacotherapies using translational, clinically relevant NHP models.