Functional Epigenetic Profiling of Anti-Relapse Cannabidiol

抗复发大麻二酚的功能表观遗传学分析

• 批准号: 9317927
• 负责人: Nobuyoshi Suto
• 金额: $ 28.88万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317927
• 关键词: Aftercare; Anatomy; Animal Model; Biological Availability; Brain; Cannabidiol; Cannabis sativa plant; Chronic; Clinical; Cocaine; Code; Cues; DNA; DNA Methylation; Development; Disease; Drug Addiction; Epigenetic Process; Fluorescence-Activated Cell Sorting; Gene Activation; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Histones; Hybrids; Knowledge; Laboratory Animals; Link; Mediating; Medical; Messenger RNA; Methodology; Methods; Modification; Molecular; Neuroglia; Neurons; Nucleus Accumbens; Opioid; Pharmaceutical Preparations; Poly A; Post-Translational Protein Processing; Proteins; Rattus; Regulator Genes; Relapse; Reporting; Research; Risk Factors; Route; Sampling; Site; Stress; Testing; Tetanus Helper Peptide; Therapeutic; Tissues; Transgenic Organisms; Translations; Vial device; alcohol seeking behavior; base; cell type; chromatin immunoprecipitation; chromatin remodeling; clinically relevant; cocaine relapse; cue reactivity; drug craving; drug modification; drug of abuse; drug relapse; epigenetic profiling; epigenome; gene repression; genome-wide; improved; interdisciplinary approach; mRNA Expression; methylation biomarker; molecular marker; neurobiological mechanism; next generation sequencing; novel; oligo (dT); relating to nervous system; response; transcriptome; transdermal cannabidiol; treatment duration

Drug addiction is a chronic relapsing disorder of compulsive drug craving, seeking and use. We have identified a substantial therapeutic potential of cannabidiol (CBD) – a non-psychoactive compound naturally occurring in the cannabis sativa plant – against drug relapse. A 7-day treatment of CBD via a clinically relevant transdermal route reduced both cue- and stress-triggered reinstatement of cocaine as well as alcohol seeking in rats – well- established animal models of drug relapse. Taken together with relevant reports on opioids, CBD appears to be effective against two major modes of relapse-promotion across three major classes of drugs of abuse. While the underlying neurobiological mechanism is still unclear, CBD's anti-relapse action (still evident at 138 days post-treatment) greatly outlasted its bioavailability (<18 days). It is thus likely that molecular alterations – via long-lasting epigenetic modifications – underlie the prolonged anti-relapse action of CBD. Previous studies have identified CBD-triggered molecular alterations in samples derived from homogenized tissues of the nucleus accumbens (NAc) – a brain site well-implicated in drug relapse. Available evidence however indicates that cue-triggered responses – such as drug craving and seeking – are mediated by `cue-reactive (activated)' rather than `non-reactive' neurons in NAc (and other sites). Given that only a small subset (3-10%) of neurons in NAc (and other sites) are reactive to drug cues, molecular alterations identified in samples derived from homogenized tissues – that contain both cue-reactive and non-reactive neurons as well as non-neural glia – may not be functionally relevant to CBD's anti-relapse action. In contrast, long-lasting epigenetic modifications unique to neurons in which drug cue-reactivity is modulated by CBD likely mediate the prolonged anti-relapse action of CBD. Based on the scientific premise outlined above, this R21 project will test the hypothesis that “CBD exerts its prolonged anti-relapse action via epigenetic modification of drug cue-reactive neurons”. The project will take a multidisciplinary approach incorporating (1) a well-established animal model of cocaine relapse, (2) a novel strain of transgenic rats for activity-dependent neural tagging, (3) cell type-specific molecular sampling via fluorescence activated cell sorting, and (4) next-generation sequencing for comprehensive profiling of epigenetic and transcriptional markers. The primary goal is to determine the long- lasting effects of CBD on gene expression – that are both cell type-specific and activity-dependent (on drug cue-reactivity) – at the level of epigenome and protein-coding transcriptome, and thereby help elucidate the molecular mechanisms functionally linked to CBD's prolonged anti-relapse action. Another primary goal is to establish the proof of concept for the functional epigenetic profiling of CBD as a potential anti-relapse medication – a novel method that can be applied to investigate the therapeutic action of other medications. The knowledge gained through such studies then can be utilized to improve the efficacy of medical treatments via precise identification of on- and off-target effects.

药物成瘾是一种强迫性药物渴求、寻求和使用的慢性复发性障碍。我们已经确定了 大麻二酚(CBD)的巨大治疗潜力--一种天然存在于 大麻属植物--抗药物复发。经临床相关的透皮疗法治疗CBD 7天 路线减少了线索和压力触发的可卡因和酒精寻找的恢复-嗯- 建立了药物复发的动物模型。结合有关阿片类药物的报告，CBD似乎 对三大类药物滥用的两种主要模式--促进复发--有效。 虽然潜在的神经生物学机制仍不清楚，但CBD的抗复发作用(在138岁时仍很明显 治疗后天数)大大超过其生物利用度(&lt；18天)。因此，很可能是分子变化- 通过持久的表观遗传修饰--CBD持久的抗复发作用的基础。以前的研究 在取自小鼠心脏匀浆组织的样本中发现了CBD引发的分子改变 伏隔核(NAC)--一个与药物复发密切相关的大脑部位。然而，现有证据表明 线索触发的反应--如对毒品的渴求和寻求--是由“线索-反应(激活)”调节的。 而不是NAC(和其他部位)的“非反应性”神经元。鉴于只有一小部分神经元(3%-10%) 在NAC(和其他部位)对药物线索有反应，从以下来源的样品中识别出分子变化 均质组织--既包含线索反应性神经元，也包含非反应性神经元以及非神经性胶质细胞-- 可能在功能上与CBD的抗复发行动无关。相比之下，长期的表观遗传修饰 CBD调节药物线索反应性的神经元所特有的可能介导延长的抗复发 CBD的行动。基于上面概述的科学前提，这个R21项目将检验以下假设 CBD通过药物线索反应神经元的表观遗传修饰发挥其长期的抗复发作用。这个 该项目将采用多学科方法，包括(1)已建立的可卡因动物模型 复发，(2)用于活动依赖神经标记的转基因大鼠的新品系，(3)细胞类型特异性 通过荧光激活的细胞分选进行分子采样，以及(4)用于 表观遗传和转录标记的综合分析。主要目标是确定长期- CBD对基因表达的持久影响--既是细胞类型特异的，也是活性依赖的(取决于药物 提示反应性)-在表观基因组和蛋白质编码转录组的水平上，从而有助于解释 与CBD延长抗复发作用有关的分子机制。另一个主要目标是 为CBD的功能性表观遗传学特征作为潜在的抗复发药物建立概念证明 药物治疗--一种可用于研究其他药物治疗作用的新方法。这个 通过这种研究获得的知识可以用来通过以下途径提高医疗效果 精确识别目标上和目标外的效果。