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）：酒精中毒的特征是个人无法适当地调节酒精的消费。大量证据将多巴胺能遗传标记（例如DRD2 Taqia多态性调节）调节多巴胺受体的功能和/或表达，与发展酗酒的风险增加（Noble等，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在28位白人男性社会饮酒者中。对于DAT，将使用具有9/9或10/10基因型的亚组来检查3'非翻译区域（SLC6A3）的串联重复（VNTR）多态性的可变数。 COMT（Catechol-O-甲基转移酶）亚组将根据Val/Val（快速代谢物）或MET等位基因（低代谢剂）进行划分，DRD2 TAQIA A1亚组将分为A1+和A1-和A1-和A1-和A1-参与者和EXON 3中的DRD4 VNTR，将其分成几个以外的7个vntr。我们将社交饮酒者的DA D2型受体的供应与上述等位基因的副本与没有两个条件的人进行比较； 1.）摄入酒精饮料和2.）摄入安慰剂饮料后。我们将将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衡量纹状体D2样的多巴胺受体可用性的变化（作为对酒精的多巴胺释放的标志物的标记）[18F] FallyPride（fallypride）（基于D2类样多巴胺受体的放射性培训），以确定对基因型的差异，以确定依赖于Genotype andype andype。 我们希望与DRD2 Taqia A1等位基因的社交饮酒者，DAT，带有9个等位基因，DRD4，重复<7个等位基因，与对应物相比，val/Val/Val/val comt基因型的BPND在安慰剂扫描过程中的BPND和释放的均应降低了纹状体受体可用性的降低，因为它们的含量较大，因为它们的相对摄入后，因为它们相对摄入后，因为相对摄入剂，因为它们相对摄入了相对的摄入量。放射性示例与这些个体大脑中较少受体结合。迄今为止，尚无公开研究，研究基因型是否会影响多巴胺受体在酒精挑战期间的反应方式。 公共卫生相关性：滥用酒精的滥用和依赖仍然是全球流行病。在美国，有1,730万成年人报告了酗酒或依赖性，略多于12岁以上的美国人中有一半以上是目前的酒精饮酒者（Samhsa，2009年）。我们提出的研究将使用非侵入性的大脑成像技术来研究遗传学在大脑对酒精的反应中的作用，并可能与饮用酒精饮料相关的情绪状态；目的是确定使人们容易受到有害饮酒行为的潜在生物标志物。