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

项目总结/摘要 可卡因使用障碍（CUD）仍然是美国的一个主要公共卫生和社会问题。一 CUD的特点是易感性、复发和治疗效果的个体差异。我们的总体目标是 更好地理解强化的长期后果中的个体差异 可卡因的影响使用一个独特的非人灵长类动物模型的CUD。我们建议使用神经源性 外泌体（NDE）在血液中，以确定分子生物标志物与个人的脆弱性， 可卡因滥用，戒断后复发的易感性，以及靶向治疗的成败， 可卡因滥用外泌体是由所有细胞类型释放的纳米囊泡。这些细胞释放的 应激或病理状态不同于在正常生理条件下释放的那些。以 由于这种差异的优势，已经研究了几种基于外泌体的诊断和预后生物标志物。 成功开发。最近的研究还表明，生物流体中的外来体可用于建立 与甲基苯丙胺海洛因和酒精滥用相关的分子特征然而，外泌体具有 没有被用来理解可卡因滥用-本申请的重点。拟议的研究利用了 及时使用来自正在进行的NIDA资助研究的血浆样本（R 01 DA 017763 -11; PI： Nader）了解社会圈养的雌性和雄性猴子中的可卡因滥用。母体研究正在测试 几种药物的疗效被认为在占主导地位的和从属地位的女性不同的工作 和雄性猴子。所有猴子（群居，自然形成统治和从属等级） 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 受体（D2/D3 R）的可用性使用正电子发射断层扫描（PET）成像。关键的成本 现有资金所涵盖的措施，这些猴子的血浆样本的可用性提供了一个 这是一个宝贵的、具有成本效益的机会，可以促进我们对外来体如何提供非生物学功能的理解。 侵入性分子工具，告知我们可卡因滥用和治疗结果。试点和可行性数据（a） 验证我们从储存的血浆样本中分离和表征NDE的能力，以及（B）支持以下实用性： NDE生物标志物，以了解可卡因自我给药（SA）的分子效应，以及社会影响 对雄性和雌性猴子可卡因脆弱性和治疗结果进行排名。因此，我们建议两个 具体目标：一。描述群居男性和女性中与可卡因SA相关的NDE特征 猴子二.描述与药物治疗成功或失败相关的NDE，以减少 可卡因SA在社会圈养的男性和女性猴子。我们的成果将大大推动 对可卡因滥用脆弱性分子理解的非侵入性生物标志物的表征 和复发，并为制定治疗药物滥用的个性化医疗策略做出贡献。

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.