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

基本信息

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
项目类别：
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

项目摘要

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最近的研究表明，学习和记忆等复杂行为的基本类型是相同的。哺乳动物中药物奖励的行为在无脊椎动物（小龙虾、苍蝇、秀丽隐杆线虫）中也很明显。线虫是研究人类行为的神经生物学基础的绝佳模型：保守、完全易处理的基因组；并且世代时间短，维护成本低，可实现快速世代我们已经证明，秀丽隐杆线虫表现出条件反射。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我们还发现线虫表现出向和的运动。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))，这被认为是一种“偏好反应”，最近在秀丽隐杆线虫中发现了阿片受体。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我们测试了阿片类拮抗剂纳曲酮的效果和有效治疗方法。 AUD 和其他成瘾，对秀丽隐杆线虫的 EtOH 偏好，纳曲酮治疗可阻断急性 EtOH 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）的吸引力没有影响慢性乙醇暴露增强了乙醇偏好，诱导治疗抵抗和强迫性- 在厌恶刺激下持续自我暴露于乙醇所证明的类似行为（壬酮）。这些数据共同表明线虫有潜力作为识别模型系统。然而，需要明确的证据来充分治疗 AUD 和其他成瘾性疾病。表征模型并确认迄今为止观察到的现象与因此，本申请的目的是测试先前显示可减少 AUD 的化合物。脊椎动物模型中的 EtOH 饮用和/或寻求，在急性和急性期秀丽隐杆线虫 EtOH 偏好测试中慢性模型，并表征反应的选择性，结果预计将表明：抑制乙醇药物和人类复发的乙醇药物消耗也会对秀丽隐杆线虫产生类似的影响，其中两个物种之间介导反应的药理学和分子系统相似。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为了提高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的转基因线虫和药理学的建立。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。