The Influence of Dopaminergic Genetic Variants on D2-like Receptors in Drinkers

多巴胺能遗传变异对饮酒者 D2 样受体的影响

• 批准号: 8064818
• 负责人: Amira K Brown
• 金额: $ 3.85万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064818
• 关键词: 3' Untranslated Regions; Acute; Adult; Affect; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Beverages; Alcoholism; Alcohols; Alleles; American; Beverages; Binding; Biological Markers; Brain; Brain imaging; Candidate Disease Gene; Catechol O-Methyltransferase; Code; Corpus striatum structure; DRD2 gene; DRD4 gene; Data; Dependence; Dopamine; Dopamine Receptor; Dose; Emotional; Epidemic; Exons; Foundations; Frequencies; Funding; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Grant; Imaging Techniques; Individual; Intention; Japanese Population; Juice; Label; Link; Measures; Minisatellite Repeats; Moods; Oranges; Parents; Participant; Patient Self-Report; Pilot Projects; Placebos; Play; Population; Positron-Emission Tomography; Prevalence; Publishing; Receptor Gene; Recruitment Activity; Relative (related person); Reporting; Research Personnel; Risk; Role; Scanning; Seizures; Subgroup; Substance abuse problem; Testing; Trust; United States; United States National Institutes of Health; United States Substance Abuse and Mental Health Services Administration; Variant; Withdrawal; alcohol response; base; dopamine system; drinking; drinking behavior; genetic variant; instrument; male; meetings; negative mood; positive mood; problem drinker; public health relevance; radiotracer; receptor; social; valylvaline

DESCRIPTION (provided by applicant): Alcoholism is characterized by the inability of individuals to regulate their consumption of alcohol appropriately. Considerable evidence links dopaminergic genetic markers like the DRD2 TaqIA polymorphism, which modulates the function and/or expression of dopamine receptors, to the increased risk for developing alcoholism (Noble et al., 2003). The aims of the proposed pilot study are to acquire preliminary data needed to apply for an NIH grant to assess the relationship between the dopaminergic genetic variants DRD2 TaqIA A1 allele, COMT Val/Val vs. Met, DRD4 VNTR 7-repeat allele and DAT VNTR SCL39 9-repeat (vs. the 10-repeat allele), with central response to alcohol, and associated self-reported mood states in twenty-eight white male social drinkers. For DAT, the variable number of tandem repeat (VNTR) polymorphism of the 3' untranslated region (SLC6A3) will be examined with subgroups that have either the 9/9 or the 10/10 genotype; COMT (catechol-O- methyltransferase) subgroups will be divided based on Val/Val (rapid metabolizers) or Met allele (low metabolizers), DRD2 TaqIA A1 subgroups will be separated into A1+ and A1- participants and the DRD4 VNTR in exon 3 will be separated into subgroups that have either greater or fewer than the 7-repeat allele. We are comparing DA D2-like receptor availability in social drinkers with copies of the above mentioned alleles to those without under two conditions; 1.) after ingesting an alcoholic beverage and 2.) after ingesting a placebo beverage. We will contrast the allelic groups with how alcohol alters self-reported mood and use positron emission tomography to measure changes in striatal D2-like dopamine receptor availability (as a marker for dopamine release in response to alcohol) with [18F]fallypride (a radiotracer for D2-like dopamine receptors) to determine whether differences exist based on genotype in response to an alcohol challenge. We expect that the social drinkers with the DRD2 TaqIA A1 allele, DAT with 9 alleles, DRD4 with <7 repeats and the Val/Val COMT genotypes, as compared with their counterparts, will have lower BPND for the radiotracer during the placebo scan and a greater reduction in striatal receptor availability after ingestion of alcohol, relative to their counterparts because, released dopamine will compete with the radiotracer for binding to fewer receptors in the brains of these individuals. To date, there are no published studies examining whether genotype affects the way dopamine receptors respond during an alcohol challenge. PUBLIC HEALTH RELEVANCE: The abuse of and dependence on alcohol continues to be a worldwide epidemic. In the United States 17.3 million adults reported alcohol abuse or dependence and slightly more than half of Americans aged 12 or older reported being current drinkers of alcohol (SAMHSA, 2009). Our proposed study will use non-invasive brain imaging techniques to investigate the role that genetics play in the brain's response to alcohol and possibly the emotional states associated with consuming an alcoholic beverage; with the intention of identifying potential biomarkers that make people vulnerable to harmful drinking behaviors.

描述（由申请人提供）：酒精中毒的特点是个人无法适当地调节他们的酒精消费。相当多的证据将多巴胺能遗传标志物如DRD 2 TaqIA多态性（其调节多巴胺受体的功能和/或表达）与发生酒精中毒的风险增加联系起来（Noble et al.，2003年）。 拟议的初步研究的目的是获得申请NIH资助所需的初步数据，以评估多巴胺能遗传变异DRD 2 TaqIA A1等位基因、COMT瓦尔/瓦尔vs. Met、DRD 4 VNTR 7-重复等位基因和DAT VNTR SCL 39 9-重复之间的关系（与10重复等位基因），与酒精的中枢反应，并在28个白色男性社交饮酒者自我报告的情绪状态。对于DAT，将用具有9/9或10/10基因型的亚组检查3'非翻译区（SLC 6A 3）的可变数目串联重复（VNTR）多态性; COMT（儿茶酚-O-甲基转移酶）亚组将根据瓦尔/瓦尔进行划分（快速代谢型）或Met等位基因（低代谢者），DRD 2 TaqIA A1亚组将分为A1+和A1-参与者和外显子3中的DRD 4 VNTR将被分成具有大于或小于7个重复等位基因的亚组。我们在两种条件下比较了具有上述等位基因拷贝的社交饮酒者与不具有上述等位基因拷贝的社交饮酒者中的DA D2样受体可用性; 1.）在摄入酒精饮料后，以及2.）服用安慰剂饮料后。我们将对比等位基因组与酒精如何改变自我报告的情绪，并使用正电子发射断层扫描来测量纹状体D2样多巴胺受体可用性（作为响应酒精的多巴胺释放的标志物）与[18 F]fallypride（D2样多巴胺受体的放射性示踪剂）的变化，以确定是否存在基于基因型的差异。 我们预计，与他们的对应物相比，具有DRD 2 TaqIA A1等位基因、具有9个等位基因的DAT、具有<7个重复的DRD 4和瓦尔/瓦尔COMT基因型的社交饮酒者在安慰剂扫描期间将具有较低的放射性示踪剂BPND，并且相对于他们的对应物，摄入酒精后纹状体受体可用性的降低更大，因为，释放的多巴胺将与放射性示踪剂竞争结合到这些个体脑中较少的受体上。到目前为止，还没有发表的研究来研究基因型是否会影响多巴胺受体在酒精挑战中的反应。 公共卫生相关性：酒精滥用和依赖仍然是一种世界性的流行病。在美国，有1730万成年人报告有酒精滥用或依赖，12岁或12岁以上的美国人中有一半以上报告目前饮酒（SAMHSA，2009年）。我们提出的研究将使用非侵入性脑成像技术来调查遗传学在大脑对酒精的反应中所起的作用，以及可能与消费酒精饮料相关的情绪状态;目的是确定使人们容易受到伤害的潜在生物标志物。