A novel and powerful C. elegans behavioral model of addiction

一种新颖而强大的线虫成瘾行为模型

• 批准号: 8488832
• 负责人: ERIC A. ENGLEMAN
• 金额: $ 19.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488832
• 关键词: Accidents; Affect; Amphetamines; Animal Model; Antineoplastic Agents; Astacoidea; Basic Science; Behavior; Behavioral; Behavioral Assay; Behavioral Model; Biological Assay; Biological Models; Caenorhabditis elegans; Caffeine; Cessation of life; Characteristics; Chemotaxis; Cocaine; Complex; Cues; Data; Data Analyses; Data Collection; Development; Disease; Drug Addiction; Ethanol; Exposure to; Extinction (Psychology); Foundations; Frequencies; Future; Gene Proteins; Generations; Genes; Homicide; Homologous Gene; Human; Invertebrates; Learning; Maintenance; Mammals; Maps; Measurement; Measures; Mediating; Memory; Methamphetamine; Modeling; Molecular; Molecular Genetics; Molecular Target; Movement; Mus; Neurobiology; Neuromodulator; Neurons; Neurotransmitters; Nicotine Dependence; Organism; Overdose; Pharmaceutical Preparations; Pharmacology; Prevention; Productivity; Property; Psychotropic Drugs; RNA Interference; Rattus; Reporting; Rewards; Salts; Second Messenger Systems; Synapses; System; Technology; Testing; Time; Vertebrates; War; Work; addiction; base; conditioning; cost; driving under influence; drug craving; drug of abuse; drug reward; effective therapy; fly; follow-up; food restriction; genome sequencing; mesolimbic system; mutant; novel; preference; public health relevance; research study; response; translational approach

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.

描述（由申请人提供）：吸毒成瘾是一种严重且代价高昂的疾病，人们对此知之甚少，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。无脊椎动物的基础研究在揭示学习和记忆等复杂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、线虫）中也很明显。线虫是研究人类行为神经生物学基础的绝佳模型，它具有：令人惊讶的保守性、完全测序的基因组，可以轻松操作；完整映射的神经解剖系统；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体的一小部分。线虫表现出对各种精神活性药物（包括可卡因、甲基苯丙胺、乙醇和咖啡因）的运动和浓度依赖性自我暴露。我们发现它们在药物预暴露后也表现出致敏、耐受、交叉致敏和交叉耐受。此外，我们最近报道，线虫对先前与可卡因或甲基苯丙胺配对的线索（盐）表现出条件性偏好，这类似于哺乳动物药物奖励模型中的发现。这些数据共同表明，线虫可以作为研究滥用药物的优秀行为模型系统，具有揭示成瘾潜在分子基础的巨大潜力。然而，需要明确的行为证据来完全建立线虫模型并确认迄今为止观察到的现象与哺乳动物中的发现一致。当前的应用程序将系统地检查对先前与可卡因或甲基苯丙胺相关的线索的线索条件偏好反应（CR），以确定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 CR 是否表现出持久性、消失和恢复，以及它是否受到调节试验频率、药物预暴露和/或食物限制的影响。所有这些 这些特征是哺乳动物药物奖励模型中的重要因素，预计也存在于秀丽隐杆线虫中。此外，我们还建议缩小行为测定的规模，在六孔板中进行，以便使用线虫对药物偏好和提示 CR 进行完全客观、高通量的测量。后续研究将测试哺乳动物中具有同源基因缺陷的突变线虫菌株，这些基因已被证明可以介导滥用药物的提示 CR，并且研究结果将使用药理学和/或 RNAi 技术在野生型蠕虫中得到证实。在线虫成瘾的新行为模型的建立将是该领域的变革性进步。未来的研究将利用研究秀丽隐杆线虫这些行为的机制的巨大优势。凭借识别新分子靶点的前景，以及未来应用该模型筛选用于药物开发的化合物，该项目对人类药物成瘾的治疗具有巨大的潜在影响。