A NOVEL AND POWERFUL MEDICATIONS SCREEN FOR ALCOHOL USE DISORDERS

针对酒精使用障碍的新颖而强大的药物筛查

• 批准号: 9242939
• 负责人: ERIC A. ENGLEMAN
• 金额: $ 7.84万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-20 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242939
• 关键词: Acute; Affect; Alcohol consumption; Alcohols; Animal Model; Animals; Astacoidea; Aversive Stimulus; Baclofen; Bacteria; Basic Science; Behavior; Behavior Therapy; Behavioral; Behavioral Mechanisms; Behavioral Model; Benzaldehyde; Biological Assay; Biological Models; Caenorhabditis; Caffeine; Characteristics; Chemotaxis; Chronic; Clinical Trials; Cocaine; Complex; Cues; Data; Development; Disease; Dose; Drug Addiction; Drug Modelings; Ethanol; Exhibits; Exposure to; Follow-Up Studies; Food; Foundations; Future; Generations; Genome; Goals; Human; Intake; Invertebrates; Ions; Learning; Maintenance; Mammals; Maps; Mediating; Memory; Methamphetamine; Methods; Modeling; Molecular; Motor Activity; Movement; Naloxone; Naltrexone; Narcotic Antagonists; Neurobiology; Neurotransmitters; Opioid; Opioid Receptor; Organism; Pharmaceutical Preparations; Pharmacology; Phylogenetic Analysis; Play; Preclinical Drug Evaluation; Process; Psychotropic Drugs; Reporting; Rodent Model; Role; Screening procedure; Societies; Sodium Chloride; Stimulus; System; Technology; Testing; Time; Transgenic Organisms; Translations; Treatment Efficacy; Vertebrates; Work; acamprosate; addiction; alcohol abuse therapy; alcohol exposure; alcohol relapse; alcohol screening; alcohol seeking behavior; alcohol use disorder; cost; drug reward; drug testing; effective therapy; experimental study; fly; high throughput screening; mutant; novel; preference; receptor; response; screening; therapy resistant; tool; topiramate; varenicline

Alcohol use disorders (AUDs) cause serious problems in society and few effective treatments are available. Basic research with invertebrates has provided ground-breaking discoveries in uncovering mechanisms that underlie behaviors as complex as learning and memory. Recent work indicates that the same basic types of behavior that define drug reward in mammals are also evident in invertebrates (crayfish, flies, C. elegans). C. elegans is an excellent model to study the neurobiological basis of human behavior with: a surprisingly conserved, fully tractable genome; and a short generation time with low maintenance costs for fast generation of data at a fraction of the cost of other organisms. We have shown that C. elegans display a conditioned preference for cues previously paired with cocaine or methamphetamine, analogous to findings in mammalian models of drug reward. We have also found that C. elegans demonstrate movement toward, and concentration-dependent self-exposure to various psychoactive drugs (i.e. cocaine, caffeine, and ethanol (EtOH)), which is deemed a “preference response”. The recent discovery of opioid receptors in C. elegans provided the impetus to test the hypothesis that C. elegans may be used as a medications screen to identify new treatments for AUDs. We tested the effects of naltrexone, an opioid antagonist and effective treatment for AUDs and other addictions, on EtOH preference in C. elegans. Naltrexone treatment blocked acute EtOH and cocaine preference, but had no effect on motor activity or attraction to food or benzaldehyde (a volatile attractant). Chronic EtOH exposure enhanced EtOH preference, induced treatment resistance and compulsive- like behavior as evidenced by sustained self-exposure to EtOH in the presence of an aversive stimulus (nonanone). Together these data indicate that C. elegans have potential to serve as a model system to identify compounds to treat AUDs and other addictive disorders. However, clear evidence is needed to fully characterize the model and confirm that the phenomena observed thus far are consistent with efficacy of treatments for AUDs. Thus, the objective of this application is to test compounds, previously shown to reduce EtOH drinking and/or seeking in vertebrate models, in the C. elegans EtOH preference test in acute and chronic models, and to characterize the selectivity of the response. The results are expected to show that drugs that inhibit EtOH consumption and relapse in humans will produce similar effects in C. elegans where the pharmacology and molecular systems mediating the response are similar between the two species. Follow- up studies will test mutant C. elegans to identify mechanisms involved for candidate compounds with positive treatment results. To enhance the validity and translation of the model, future projects will include creating transgenic C. elegans expressing human receptors and pharmacology. The establishment of an effective high throughput behavioral model using C. elegans to screen candidate agents to treat AUDs would be a transformational advancement in the field, and is the long-term goal of this project.

酒精使用障碍（AUDs）在社会中造成严重的问题，几乎没有有效的治疗方法。 对无脊椎动物的基础研究在揭示机制方面提供了突破性的发现， 像学习和记忆这样复杂的行为的基础。最近的研究表明，相同的基本类型的 在哺乳动物中定义药物奖励的行为在无脊椎动物中也很明显（小龙虾、苍蝇、C. elegans）。C. 线虫是研究人类行为的神经生物学基础的一个很好的模型， 保守的，完全易处理的基因组;以及短的世代时间，低的维持成本，用于快速世代 以其他生物的一小部分成本获取数据。我们证明了C.优雅的人表现出一种条件反射， 偏好先前与可卡因或甲基苯丙胺配对的线索，类似于哺乳动物中的发现 药物奖励的模型。我们还发现C.优雅的人表现出运动， 浓度依赖性的自我暴露于各种精神活性药物（即可卡因、咖啡因和乙醇 （EtOH）），其被认为是“偏好反应”。阿片受体是近年来在C. elegans 为检验C.秀丽线虫可以用作药物筛选， AUDs的新疗法。我们测试了纳洛酮的作用，纳洛酮是一种阿片类拮抗剂， AUDs和其他成瘾，在C.优雅的纳洛酮治疗阻断急性EtOH， 可卡因偏好，但对运动活动或对食物或苯甲醛（挥发性 引诱剂）。慢性乙醇暴露增强乙醇偏好，诱导治疗抵抗和强迫性- 在存在厌恶刺激的情况下持续自我暴露于EtOH证明的类似行为 （壬酮）。这些数据表明C.秀丽线虫有潜力作为一个模型系统， 治疗AUD和其他成瘾性疾病的化合物。然而，需要有明确的证据， 表征模型，并确认迄今观察到的现象与 治疗AUD。因此，本申请的目的是测试化合物，其先前显示降低 在脊椎动物模型中，在C.在急性和急性期的Elegans EtOH偏好试验 慢性模型，并表征响应的选择性。预计结果将显示， 抑制EtOH消耗和人类复发的药物将在C. elegans哪里 两个物种之间的药理学和介导反应的分子系统相似。跟着- 研究将测试突变体C elegans来确定候选化合物的机制， 治疗结果。为了提高模型的有效性和翻译，未来的项目将包括创建 转基因长表达人类受体和药理学的线虫。建立一个有效的高 吞吐量行为模型，使用C. elegans筛选候选药物治疗AUDs将是一个 这是该领域的转型进步，也是该项目的长期目标。