A NOVEL AND POWERFUL MEDICATIONS SCREEN FOR ALCOHOL USE DISORDERS

酒精使用障碍(AUD)在社会上造成了严重的问题，几乎没有有效的治疗方法。 对无脊椎动物的基础研究提供了突破性的发现，揭示了 像学习和记忆一样复杂的行为是其基础。最近的研究表明，相同的基本类型 在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。 优雅的动物是研究人类行为的神经生物学基础的极佳模型：令人惊讶的是 保守、完全可处理的基因组；快速生成需要较短的生成时间和较低的维护成本 数据的成本只有其他生物的一小部分。我们已经证明线虫表现出一种条件性的 对先前与可卡因或甲基苯丙胺配对的线索的偏好，类似于在哺乳动物中的发现 毒品奖励的典范。我们还发现，线虫表现出向 自身暴露于各种精神活性药物(如可卡因、咖啡因和乙醇)的浓度依赖性 (Etoh))，这被认为是“偏好反应”。线虫体内阿片受体的新发现 提供了检验线虫可能被用作药物筛查以识别 AUDS的新治疗方法。我们测试了纳曲酮的效果，一种阿片类拮抗剂和有效的治疗 AUDS和其他成瘾，基于线虫对乙醇的偏好。纳曲酮治疗可阻断急性无痛性脑出血 偏好可卡因，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)。慢性乙醇暴露可增强乙醇偏好、诱导治疗抵抗和强迫行为-- 类似的行为，表现为在存在令人厌恶的刺激时持续自我暴露于乙醇 (壬酮)。总之，这些数据表明线虫有潜力作为模式系统来识别 治疗AUDS和其他成瘾障碍的化合物。然而，需要明确的证据才能充分 确定模型的特征，并确认到目前为止观察到的现象与 AUDS的治疗。因此，这一应用的目的是测试化合物，先前显示的是还原 在脊椎动物模型中饮用和/或寻找乙醇，在急性和 慢性模型，并表征反应的选择性。预计结果将表明， 抑制乙醇消耗和人类复发的药物在线虫中也会产生类似的效果， 在这两个物种之间，调节反应的药理学和分子系统是相似的。以下为- UP研究将测试突变的线虫，以确定与阳性候选化合物相关的机制 治疗结果。为了增强模型的有效性和翻译性，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。建立一个有效的高 使用线虫筛选治疗AUDS的候选药物的吞吐量行为模型将是一种 这是该领域的转型进步，也是该项目的长期目标。

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.