Neuronal exosomes in cocaine abuse and treatment response in socially housed monkeys

项目摘要/摘要 可卡因使用障碍(CUD)在美国仍然是一个主要的公共卫生和社会问题。一个 CUD的特点是在易感性、复发和治疗效果方面存在个体差异。我们的总体目标是 更好地理解个人差异对强化的长期后果 使用独特的非人灵长类动物CUD模型研究可卡因的影响。我们建议使用神经元衍生的 血液中的外切体(NDE)，以识别与个体易患疟疾相关的分子生物标记物 可卡因滥用、戒除后复发的易感性以及针对以下疾病的靶向治疗的成功或失败 可卡因滥用。外切体是所有类型的细胞都能释放的纳米囊泡。由以下细胞释放的 应激或病理状态不同于正常生理条件下释放的状态。拿走 利用这种差异，几个基于外切体的诊断和预后生物标志物已经被 开发成功。最近的研究还表明，生物体液中的外切体可以用来建立 与甲基苯丙胺、海洛因和酗酒有关的分子特征。然而，外显体有 没有被用来理解可卡因滥用-这是本申请的重点。拟议的研究充分利用了 及时使用正在进行的NIDA资助研究的血浆样本(R01 DA017763-11；PI： 了解群居雌性和雄性猴子滥用可卡因的情况。家长研究正在测试 几种被认为对优势女性和从属女性起不同作用的药物的疗效 还有雄性猴子。所有猴子(在社会中居住，并自然形成主导和从属等级) 正在接受全面的行为和认知测试，以及中枢多巴胺D2/D3的神经成像 使用正电子发射断层扫描(PET)成像的受体(D2/D3R)可用性。带着钥匙的成本 现有资金涵盖的措施，这些猴子的血浆样本的可用性提供了一个 这是一次宝贵且经济高效的机会，让我们进一步了解外切体是如何提供一种 告诉我们可卡因滥用和治疗结果的侵入性分子工具。试点和可行性数据(A) 验证我们从存储的血浆样本中分离和表征NDE的能力，以及(B)支持 了解可卡因自我给药(SA)的分子效应和社会影响的NDE生物标志物 对雄性和雌性猴子的可卡因脆弱性和治疗结果进行排名。因此，我们提出了两个 具体目标：i.确定与可卡因SA相关的性骚扰在社会寄居男性和女性中的特征 猴子。二、描述与药物治疗成功或失败有关的不良反应 群居雄性和雌性猴子体内的可卡因SA。我们的结果将大大推动进展 非侵入性生物标志物在可卡因滥用易感性分子研究中的应用 和复发，并为制定治疗药物滥用的个性化药物战略做出贡献。

Project Summary/Abstract Cocaine use disorder (CUD) continues to be a major public health and social problem in the United States. A hallmark of CUD is individual differences in vulnerability, relapse and treatment efficacy. Our overall goal is to achieve a better understanding of individual differences in the long-term consequences of the reinforcing effects of cocaine using a unique nonhuman primate model of CUD. We propose to use neuronal-derived exosomes (NDE) in the blood to identify molecular biomarkers associated with an individual's vulnerability to cocaine abuse, susceptibility to relapse following abstinence, and success or failure of targeted therapies for cocaine abuse. Exosomes are nano-vesicles that are released by all cell types. Those released by cells under stressed or pathologic states are different from those released under normal physiologic conditions. Taking advantage of this difference, several exosome-based diagnostic and prognostic biomarkers have been successfully developed. Recent studies have also shown that exosomes in biofluids can be used to establish molecular signatures associated with methamphetamine, heroin, and alcohol abuse. However, exosomes have not been used to understand cocaine abuse – the focus of this application. The proposed study capitalizes on a timely opportunity to use plasma samples from an ongoing NIDA-funded study (R01 DA017763-11; PI: Nader) to understand cocaine abuse in socially housed female and male monkeys. The parent study is testing the efficacy of several pharmacological agents thought to work differently in dominant and subordinate female and male monkeys. All monkeys (socially housed and naturally forming dominant and subordinate hierarchies) are undergoing comprehensive behavioral and cognitive testing, and neuroimaging of central dopamine D2/D3 receptor (D2/D3R) availability using positron emission tomography (PET) imaging. With the costs of key measures covered by existing funding, the availability of plasma samples from these monkeys offers a valuable and cost-effective opportunity to advance our understanding of how exosomes could provide a non- invasive molecular tool to inform us about cocaine abuse and treatment outcomes. Pilot and feasibility data (a) validate our ability to isolate and characterize NDEs from stored plasma samples, and (b) support the utility of NDE biomarkers to understand the molecular effects of cocaine self-administration (SA), and effects of social ranking on cocaine vulnerability and treatment outcomes in male and female monkeys. Thus, we propose two Specific Aims: I. To characterize NDEs associated with cocaine SA in socially housed male and female monkeys. II. To characterize NDEs associated with success or failure of pharmacological agents to decrease cocaine SA in socially housed male and female monkeys. Our results will significantly advance progress toward characterization of non-invasive biomarkers for molecular understanding of cocaine abuse vulnerability and relapse, and contribute in developing a personalized-medicine strategy for treating drug abuse.