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且昂贵的疾病，人们对其了解甚少，也很少有有效的治疗方法。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，但对成瘾的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为揭示像学习和记忆这样复杂的行为的潜在机制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基本行为类型在无脊椎动物（小龙虾、苍蝇、线虫）中也很明显。秀丽隐杆线虫是研究人类行为的神经生物学基础的一个极好的模型，它具有令人惊讶的保守性，完全测序的基因组可以很容易地操纵；完整的神经解剖系统；它的生成时间短，维护成本低，可以快速生成数据，而成本只是许多其他生物的一小部分。秀丽隐杆线虫对包括可卡因、甲基苯丙胺、乙醇和咖啡因在内的各种精神药物表现出运动倾向和浓度依赖性。我们发现它们在药物预暴露后也表现出致敏、耐受性、交叉致敏和交叉耐受性。此外，我们最近报道秀丽隐杆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的发现。总之，这些数据表明秀丽隐杆线虫可以作为一个很好的行为模型系统来研究药物滥用，具有揭示成瘾的潜在分子基础的巨大潜力。然而，需要明确的行为证据来充分建立秀丽隐杆线虫模型，并证实迄今为止观察到的现象与哺乳动物的发现一致。目前的应用程序将系统地检查线索条件偏好反应（CR）对先前与可卡因或甲基苯丙胺相关的线索，以确定在哺乳动物中存在的一些关键特征是否也存在于秀丽隐杆线虫中。我们将确定秀丽隐杆线虫对兴奋剂的反应是否表现出持续、消失和恢复，以及它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

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.