Ethanol Preference in C. elegans

线虫对乙醇的偏好

• 批准号: 7875265
• 负责人: STEVEN LEE MCINTIRE
• 金额: $ 9.56万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-05 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875265
• 关键词: Acute; Alcohol dependence; Animals; Behavior; Behavioral; Biochemical Pathway; Biological Assay; Biological Models; Caenorhabditis elegans; Chronic; Complex; Control Animal; Defect; Dependence; Development; Dopamine; Drug Delivery Systems; Employee Strikes; Ethanol; Exhibits; Exposure to; Felis catus; Genes; Genetic; Genetic Models; Genetic Variation; Goals; Homologous Gene; Homologous Protein; In Vitro; Individual; Intention; Ion Channel; Lead; Maps; Mediating; Modification; Molecular; Molecular Mechanisms of Action; Mus; Mutation; Organism; Pathway interactions; Pattern; Pharmaceutical Preparations; Potassium Channel; Protein C; Protein Subunits; Proteins; Research; Resistance; Serotonin; System; Testing; Time; Vertebrates; Work; alcohol effect; alcohol exposure; alcohol response; alcohol seeking behavior; alcohol sensitivity; genetic analysis; insight; large-conductance calcium-activated potassium channels; mutant; neurochemistry; novel; preference; protein function; public health relevance; receptor; relating to nervous system; response; tool

DESCRIPTION (provided by applicant): Ethanol is one of the most widely abused substances in the world, yet the molecular mechanisms of action of ethanol are poorly understood. Ethanol has been shown to disrupt ion channel functions in vitro through interactions with hydrophobic domains of channel subunit proteins and an understanding of the mechanisms that are likely to underlie some of the acute effects of ethanol has begun to emerge. It is still unclear, however, how many of the more complex behavioral responses to ethanol, such as tolerance and dependence, are mediated at a molecular level. We have pursued studies in C. elegans, as a model system, to understand the different molecular mechanisms of action of ethanol. Through genetic studies, we have identified proteins that are targets of ethanol or required for normal ethanol responses of C. elegans. In many cases, homologous proteins are also thought to be required for behavioral responses to ethanol in mammalian systems. We have demonstrated and characterized a form of acute tolerance in C. elegans that can be observed during sustained but brief ethanol exposures. After more prolonged exposure to ethanol and development of tolerance, wild type animals exhibit an intriguing change in their behavior that consists of an "ethanol-seeking" response, which we have quantified in a preference-type assay. This change is strengthened with longer ethanol exposures of several days. We have demonstrated that this response is partially dependent on dopaminergic and serotonergic function, as mutants with known defects in dopamine or serotonin synthesis exhibit substantially reduced ethanol-seeking. In addition, we have identified two novel mutants that are defective in the development of ethanol-seeking behavior. These ethanol-seeking defective mutants (esd-1 and esd-2) are also defective in the development of tolerance to ethanol. A subset of mutants defective in ethanol tolerance are found to be defective in ethanol seeking behavior, suggesting that the molecular mechanisms underlying the development of tolerance and ethanol-seeking behavior partially overlap. We now propose to complete the mapping of esd-1 and esd-2 and to clone and characterize the corresponding genes to gain insight into the molecular mechanisms that underlie this change in the desirability of ethanol over time. We will also pursue further detailed characterizations of the ethanol seeking response in wild type animals, and we will test additional mutants for defects in ethanol-seeking, as observed with esd-1 and esd-2. The determination of novel molecular mechanisms that underlie ethanol-seeking in C. elegans may enhance our understanding of changes in ethanol preference in vertebrate systems. PUBLIC HEALTH RELEVANCE: This project seeks to identify and characterize at a molecular level the mechanisms that underlie ethanol- seeking behavior in C. elegans or changes in the desirability of ethanol. Such mechanisms may be conserved. A greater understanding of the molecular pathways mediating such behavioral changes could lead to the development of medications to treat individuals who are alcohol dependent.

描述（由申请人提供）：乙醇是世界上最广泛的滥用物质之一，但是乙醇作用的分子机制知之甚少。乙醇已被证明通过与通道亚基蛋白的疏水结构域相互作用来破坏离子通道在体外的功能，并了解可能是乙醇的某些急性作用的机制已开始出现。然而，尚不清楚，有多少对乙醇的行为反应有多少，例如耐受性和依赖性，是在分子水平上介导的。我们已经在秀丽隐杆线虫作为模型系统中进行了研究，以了解乙醇的不同分子机理。通过遗传研究，我们确定了是乙醇靶标的蛋白质或秀丽隐杆线虫正常乙醇反应所必需的蛋白质。在许多情况下，哺乳动物系统中对乙醇的行为反应还需要同源蛋白。我们已经证明并表征了秀丽隐杆线虫中一种急性耐受性的形式，可以在持续但短暂的乙醇暴露期间观察到。在长期暴露于乙醇和耐受性的发展之后，野生型动物的行为发生了令人着迷的变化，其中包括“寻求乙醇”的反应，我们已经在偏好类型的测定中进行了量化。几天的乙醇暴露较长，可以加强这种变化。我们已经证明，这种反应部分取决于多巴胺能和5-羟色胺能功能，因为在多巴胺或5-羟色胺合成中具有已知缺陷的突变体显着降低了寻求乙醇的降低。此外，我们已经确定了两个新型突变体，它们在寻求乙醇行为的发展中有缺陷。这些寻求乙醇的有缺陷突变体（ESD-1和ESD-2）在对乙醇的耐受性的发展方面也有缺陷。发现乙醇耐受性有缺陷的突变体的子集在寻求乙醇的行为中有缺陷，这表明耐受性发展和寻求乙醇行为的分子机制部分重叠。现在，我们建议完成ESD-1和ESD-2的映射，并克隆并表征相应的基因，以深入了解乙醇随着时间的推移的这种变化的分子机制。我们还将对野生型动物的乙醇寻求反应进行进一步的详细特征，并将测试其他突变体是否在寻求乙醇的缺陷中，如ESD-1和ESD-2所观察到的那样。在秀丽隐杆线虫中寻求乙醇的新型分子机制的确定可能会增强我们对脊椎动物系统乙醇偏好变化的理解。 公共卫生相关性：该项目旨在在分子层面识别和表征和表征乙醇在秀丽隐杆线虫中寻求行为的机制或乙醇可取性的变化。这种机制可能是保守的。对介导这种行为变化的分子途径有更深入的了解可能导致进化用于治疗依赖酒精的人的药物。