Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction.
Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction.
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DOI：
10.1016/bs.pmbts.2015.10.019
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发表时间：
2016
影响因子：
--
通讯作者：
Neal-Beliveau BS
中科院分区：
文献类型：
--
作者：
Engleman EA;Katner SN;Neal-Beliveau BS
吸毒成瘾给社会造成了巨大的损失。需要新的动物模型来测试新的治疗方法并了解成瘾的基本机制。啮齿动物模型已经确定了与成瘾行为有关的神经回路，并表明啮齿动物具有一些与人类成瘾相同的神经生物学机制。最近的研究表明，成瘾在机制和系统发育上是古老的，人类成瘾的许多机制也存在于无脊椎动物中。秀丽隐杆线虫具有保守的神经生物学系统，具有强大的分子和遗传工具和快速的发展速度，使成本效益的转化发现成为可能。越来越多的证据表明，秀丽隐杆线虫是鉴定介导药物诱导行为的分子机制和开发各种成瘾化合物药物的潜在靶点的极好模型。秀丽隐杆线虫发出的许多行为可以很容易地量化，包括一些涉及与环境的相互作用。乙醇（EtOH）是秀丽隐杆线虫中研究最多的滥用药物，至少有50种不同的基因/靶点被确定为介导EtOH的作用，人类一些同源物的多态性与酒精使用障碍有关。秀丽隐杆线虫也显示出多巴胺和胆碱能系统依赖性对尼古丁的吸引力，并表现出对先前与尼古丁相关的线索的偏好。可卡因和甲基苯丙胺已被发现在秀丽隐杆线虫中产生多巴胺依赖的奖励行为。这些行为测试与遗传/分子操作相结合，已经鉴定出秀丽隐杆线虫中介导药物作用的数十个靶基因/系统。在所有药物滥用中，对药物诱导的行为反应至关重要的一个目标/基因是编码酪氨酸羟化酶的cat-2基因，这与多巴胺神经传递在人类成瘾中的作用是一致的。总的来说，秀丽隐杆线虫可以用来模拟药物成瘾的各个方面，并确定介导药物作用的系统和分子机制。这些发现与高级生物体的类似发现惊人地一致。此外，模型的改进是必要的，以提高模型的有效性和增加药物开发的效用。
Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH’s effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system–dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission in human addiction. Overall, C. elegans can be used to model aspects of drug addiction and identify systems and molecular mechanisms that mediate drug effects. The findings are surprisingly consistent with analogous findings in higher-level organisms. Further, model refinement is warranted to improve model validity and increase utility for medications development.