Sensitivity to Intravenous Ethanol: Genetic Determinants

对静脉注射乙醇的敏感性：遗传决定因素

• 批准号: 7503999
• 负责人: KENT E. HUTCHISON
• 金额: $ 34.96万
• 依托单位: THE MIND RESEARCH NETWORK
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7503999
• 关键词: Acute; Address; Affect; Affective; Alcohol abuse; Alcohol dependence; Alcohols; Alleles; Behavioral; Biological; CNR1 gene; Clinical; Complex; Condition; Confounding Factors (Epidemiology); Cues; Data; Development; Diagnostic; Drug Kinetics; Drug abuse; Ethanol; Etiology; Euphoria; Exons; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Human Genome; Individual; Infusion procedures; Intravenous; Literature; Measures; Methodology; Moods; National Institute on Alcohol Abuse and Alcoholism; Neurons; Opiates; Opioid Receptor; Oral; Oral Administration; Pharmacodynamics; Pharmacotherapy; Phenotype; Physiological; Prevention; Protocols documentation; Receptor Gene; Recording of previous events; Research; Saline; Sedation procedure; Testing; Variant; Work; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; base; cannabinoid receptor; craving; design; drinking; endophenotype; gene environment interaction; genetic risk factor; genetic variant; hedonic; improved; neurobiological mechanism; problem drinker; theories

DESCRIPTION (provided by applicant): The alcohol-related phenotypes that are commonly used in genetic studies are often based on broadly defined diagnostic criteria. We have focused our previous research on the development of intermediate phenotypes, or endophenotypes, that are more proximal to the biological mechanisms that underlie the etiology of alcohol dependence (e.g., acute effects of alcohol). The extant literature as well as our own previous studies clearly suggests that < opiate receptors and the < opiate receptor gene (OPRM1) are important in terms of the acute effects of alcohol. Likewise, our preliminary data indicate that cannabinoid (CB1) receptors and the cannabinoid receptor gene (CNR1) strongly influence affective responses to alcohol. The first aim of the proposed research is to replicate and extend our previous research by testing whether a functional SNP (A118G) in the OPRM1 influences the effects of an acute infusion of alcohol, as compared to a saline infusion, on physiological and subjective measures of stimulation, sedation, and mood. The first aim will also test whether this effect is specific to alcohol dependent individuals by comparing alcohol dependent individuals with healthy, non-dependent drinkers. The second aim will replicate and extend our research on the CNR1 by testing whether a functional SNP in the CNR1 influences acute responses to alcohol and whether this effect is more pronounced among alcohol dependent individuals. Finally, the third aim will examine the additive effects of these two SNPs. The proposed study is designed to both build on the strengths and address the limitations of our previous work by utilizing an alcohol infusion protocol (i.e., clamping protocol) to reduce unwanted pharmacokinetic and pharmacodynamic variability across individuals, thereby improving the overall power to detect the effects of the genetic variants and their interaction. In addition, the proposed research will address the limitations of our previous work by using a saline control condition and by testing both alcohol dependent and healthy non- dependent controls. These design improvements will allow us to examine whether or not the effect of genetic variants in the OPRM1 and CNR1 have an immediate effect on responses to alcohol or whether these variants interact with repeated exposure to alcohol to produce an enhanced sensitivity to the effects of alcohol (i.e., a gene by environment interaction) that is more evident in alcohol dependent individuals. Despite rapid advances in our understanding of the human genome, the identification of genetic factors that influence the etiology and treatment of alcohol dependence has yet to materialize. This research is designed to identify specific genetic variations that are related to how people respond to alcohol and identify how they are related to alcohol dependence. Improvements in our understanding of genetic factors and neurobiological mechanisms that influence the etiology of alcohol dependence is expected to have implications for new prevention and treatment approaches.

描述（由申请人提供）：遗传研究中常用的与酒精相关的表型通常基于广泛定义的诊断标准。我们以前的研究将重点放在中间表型或内型型的发展上，这些表型更靠近酒精依赖病因的生物学机制（例如，酒精的急性影响）。现存的文献以及我们自己以前的研究清楚地表明，<鸦片受体和<鸦片受体基因（OPRM1）在酒精的急性作用方面很重要。同样，我们的初步数据表明大麻素（CB1）受体和大麻素受体基因（CNR1）强烈影响对酒精的情感反应。拟议研究的第一个目的是通过测试OPRM1中的功能性SNP（A118G）是否会影响急性输注酒精的影响，与盐水输注，对生理学和主观刺激，镇静和情绪的生理和主观测量相比，使用功能性SNP（A118G）是否会影响急性输注酒精的影响。第一个目的还将通过比较依赖酒精的人与健康，非依赖性饮酒者来测试这种效果是否针对依赖酒精的人。第二个目标将通过测试CNR1中的功能性SNP是否影响对酒精的急性反应，以及在依赖酒精的个体中是否更明显，将复制和扩展我们对CNR1的研究。最后，第三个目标将检查这两个SNP的添加效应。拟议的研究旨在通过利用酒精输注方案（即夹紧方案）来降低个人的不良药代动力学和药效学变异性，从而提高了整体能力，从而提高了遗传变体及其相互作用的影响，旨在既依靠优势并解决我们先前工作的局限性。此外，拟议的研究将通过使用盐水控制条件并测试依赖酒精和健康的非依赖对照来解决我们先前工作的局限性。这些设计改进将使我们能够检查OPRM1和CNR1中遗传变异的影响是否对酒精反应有直接的影响，或者这些变体是否与重复暴露于酒精相互作用，以增强对酒精影响的敏感性（即环境相互作用的基因相互作用），这在酒精依赖的个人中更为相关。尽管我们对人类基因组的理解取得了迅速的进步，但影响了对酒精依赖的病因和治疗的遗传因素的鉴定尚未实现。这项研究旨在确定与人们对酒精反应的反应并确定其与酒精依赖性相关的特定遗传变异。我们对影响酒精依赖病因的遗传因素和神经生物学机制的理解有望对新的预防和治疗方法产生影响。