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 (AUD) 会造成严重的社会问题，并且几乎没有有效的治疗方法。 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 是学习和记忆等复杂行为的基础。最近的工作表明，相同的基本类型 哺乳动物中定义药物奖励的行为在无脊椎动物（小龙虾、苍蝇、线虫）中也很明显。 C. 线虫是研究人类行为的神经生物学基础的绝佳模型： 保守的、完全易于处理的基因组；发电时间短，维护成本低，可实现快速发电 数据的成本只是其他生物体的一小部分。我们已经证明线虫表现出条件性 对先前与可卡因或甲基苯丙胺配对的线索的偏好，类似于哺乳动物的发现 药物奖励模型。我们还发现线虫表现出朝向和 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))，这被视为“偏好反应”。最近在秀丽隐杆线虫中发现阿片受体 提供了动力来检验秀丽隐杆线虫可用作药物筛选来识别的假设 澳元的新疗法。我们测试了纳曲酮（一种阿片类拮抗剂）的效果和有效治疗方法 AUD 和其他成瘾，关于线虫对 EtOH 的偏好。纳曲酮治疗可阻断急性乙醇和 可卡因偏爱，但对运动活动或对食物或苯甲醛（一种挥发性物质）的吸引力没有影响 引诱剂）。慢性乙醇暴露增强了乙醇偏好，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乙醇所证明的类似行为 （壬酮）。这些数据共同表明，秀丽隐杆线虫有潜力作为模型系统来识别 治疗 AUD 和其他成瘾性疾病的化合物。然而，需要明确的证据来充分 表征模型并确认迄今为止观察到的现象与 AUD 的治疗。因此，本申请的目的是测试先前显示可以减少的化合物 脊椎动物模型中的 EtOH 饮用和/或寻求，在急性和急性期的线虫 EtOH 偏好测试中 慢性模型，并表征反应的选择性。预计结果表明 抑制人类乙醇消耗和复发的药物也会对秀丽隐杆线虫产生类似的效果，其中 两个物种之间介导反应的药理学和分子系统相似。跟随- 后续研究将测试突变型秀丽隐杆线虫，以确定具有阳性结果的候选化合物所涉及的机制 治疗结果。为了增强模型的有效性和转化性，未来的项目将包括创建 表达人类受体和药理学的转基因线虫。建立有效的高 使用秀丽隐杆线虫筛选治疗 AUD 的候选药物的吞吐量行为模型将是一个 该领域的变革性进步，是该项目的长期目标。