A novel and powerful C. elegans behavioral model of addiction

描述（由申请人提供）：药物成瘾是一种严重和昂贵的疾病，人们对它的了解很少，有效的治疗方法也很少。尽管动物模型已经开始提供有关成瘾神经生物学某些方面的重要信息，但对成瘾基本分子基础的理解仍然难以捉摸。对无脊椎动物的基础研究在揭示像学习和记忆这样复杂的行为的潜在机制方面提供了突破性的发现。最近的研究表明，在哺乳动物中定义药物奖励的相同基本行为类型在无脊椎动物（小龙虾，苍蝇，秀丽隐杆线虫）中也很明显。C.秀丽线虫是研究人类行为的神经生物学基础的极好模型，其具有：令人惊讶的保守的、完全测序的基因组，其可以容易地操纵;完全映射的神经解剖学系统;以及用于快速生成数据的短生成时间和低维护成本，其成本是许多其他生物的一小部分。C.秀丽线虫表现出向包括可卡因、甲基苯丙胺、乙醇和咖啡因在内的各种精神活性药物的运动和浓度依赖性的自我暴露。我们发现，它们在药物预暴露后也表现出致敏性、耐受性、交叉致敏性和交叉耐受性。此外，我们最近报道了C.秀丽线虫对先前与可卡因或甲基苯丙胺配对的线索（盐）表现出条件偏好，这类似于哺乳动物药物奖励模型中的发现。这些数据表明C.秀丽线虫可以作为一个很好的行为模型系统来研究药物滥用，具有巨大的潜力来揭示成瘾的潜在分子基础。然而，需要明确的行为证据来完全建立C。elegans模型，并证实迄今观察到的现象与哺乳动物中的发现一致。目前的应用程序将系统地检查提示条件偏好反应（CR），以确定是否存在于哺乳动物中的一些关键特征也存在于C。优雅我们将确定是否CR兴奋剂在C。线虫表现出持久性、灭绝性和恢复性，以及是否受到条件反射试验频率、药物预暴露和/或食物限制的影响。所有这些 特征是哺乳动物中药物奖赏模型的重要因素，并且预期也存在于C.优雅此外，我们还建议缩小行为测定的规模，使其在六孔板中进行，以实现完全客观的，高通量的药物偏好和线索CR测量使用C。优雅后续研究将测试突变体C。在哺乳动物中同源基因缺陷的线虫菌株，已显示介导对滥用药物的线索-CR，并且将使用药理学和/或RNAi技术在野生型蠕虫中证实这些发现。建立了一种新的成瘾行为模型。elegans将是该领域的一个变革性进步。未来的研究将利用研究C中支持这些行为的机制的巨大优势。优雅随着新的分子靶点的发现以及该模型在药物开发中的应用前景的前景，该项目对人类药物成瘾的治疗具有巨大的潜在影响。

DESCRIPTION (provided by applicant): Drug addiction is a serious and costly disorder that is poorly understood with few effective treatments. Although animal models have begun to provide important information about some aspects of the neurobiology of addiction, an understanding of the basic molecular foundations of addiction remains elusive. Basic research with invertebrates has provided ground-breaking discoveries in uncovering the underlying mechanisms of 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 o human behavior with: a surprisingly conserved, fully sequenced genome that can be easily manipulated; a completely mapped neuroanatomical system; and a short generation time with low maintenance costs for fast generation of data at a fraction of the cost of many other organisms. C. elegans demonstrate movement toward, and concentration- dependent self-exposure to, various psychoactive drugs including cocaine, methamphetamine, ethanol and caffeine. We have found that they also show sensitization, tolerance, cross-sensitization, and cross tolerance after drug pre-exposure. In addition, we have recently reported that C. elegans display a conditioned preference for cues (salts) that had previously been paired with cocaine or methamphetamine which is analogous to findings in mammalian models of drug reward. Together these data indicate that C. elegans can serve as an excellent behavioral model system to study drugs of abuse with tremendous potential to uncover the underlying molecular foundations of addictions. However, clear behavioral evidence is needed to fully establish the C. elegans model and confirm that the phenomena observed thus far are consistent with findings in mammals. The current application will systematically examine the cue-conditioned preference response (CR) to cues previously associated with cocaine or methamphetamine to determine if some key characteristics present in mammals are also present in C. elegans. We will determine if the CR to stimulants in C. elegans shows persistence, extinction, and reinstatement, and if it i affected by conditioning trial frequency, drug pre- exposure, and/or food restriction. All of these characteristics are important factors in models of drug reward in mammals and are expected to also be present in C. elegans. In addition, we also propose to scale-down the behavioral assays to conduct them in six-well plates to enable fully objective, high throughput measurements of drug preference and cue-CRs using C. elegans. Follow-up studies would test mutant C. elegans strains with deficits in homologous genes in mammals that have been shown to mediate cue-CRs to drugs of abuse, and findings would be confirmed in wild-type worms using pharmacology, and/or RNAi technology. The establishment of a new behavioral model of addictions in C. elegans would be a transformational advancement in the field. Future studies would leverage the tremendous advantages of studying the mechanisms that underpin these behaviors in C. elegans. With the prospect of identifying new molecular targets, and the future application of this model to screen compounds for medications development, this project has a tremendous potential impact for the treatment of human drug addiction.