GABA GENES, NEUROENDOCRINE FUNCTION, ALCOHOL SENSITIVITY AND RISK FOR ALCOHOLISM

GABA 基因、神经内分泌功能、酒精敏感性和酗酒风险

• 批准号: 8174450
• 负责人: Magdalena Uhart
• 金额: $ 0.18万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8174450
• 关键词: Accounting; Acute; Address; Advertisements; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amino Acids; Anterior Pituitary Gland; Area; Arginine; Beverages; Biological Assay; Communities; Complex; Computer Retrieval of Information on Scientific Projects Database; Demography; Dependence; Development; Diagnostic; Disease; Dose; Drug usage; Exclusion Criteria; Female; Funding; Genes; Genetic; Genetic Risk; Genetic Variation; Grant; Hereditary Disease; Hour; Human; Individual; Informed Consent; Institution; Interview; Interviewer; Laboratory Study; Life; Long-Term Effects; Los Angeles; Measures; Mediating; Medical; Mental Health; Mentored Patient-Oriented Research Career Development Award; Methods; Morbidity - disease rate; Neuraxis; Neurosecretory Systems; Newspapers; Pathway interactions; Pattern; Persons; Pharmacogenetics; Phenotype; Physiological; Population; Process; Protocols documentation; Qualifying; Questionnaires; Recording of previous events; Recruitment Activity; Research; Research Ethics Committees; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Screening procedure; Somatotropin; Source; Structure; Symptoms; Telephone; Testing; United States; United States National Institutes of Health; Universities; Variant; Woman; Writing; alcohol effect; alcohol exposure; alcohol response; alcohol seeking behavior; alcohol sensitivity; alcohol use disorder; college; drinking; experience; gamma-Aminobutyric Acid; genetic association; ghrelin; innovation; interest; male; men; mortality; receptor; relating to nervous system; response; sleep onset; social; young adult

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This protocol represents the aims of an NIH K23 Mentored Patient-Oriented Research Career Development Award. Under this protocol, subjects will participate in a comprehensive characterization of acute subjective, physiological and neuroendocrine responses to acute alcohol administration. This protocol will accomplish the following specific aims: 1. To examine if genetic variation in GABAA -receptor subunit genes mediate, in part, the observed variance in sensitivity to alcohol in a healthy social-drinking population. 2. To examine the physiological, subjective and neuroendocrine responses to acute alcohol administration in a healthy social-drinking population. RATIONALE Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. It is estimated that approximately 14% of men and 5% of women in the United States will experience the symptoms of alcohol abuse or dependence sometime in their lives. There is clear evidence that alcohol use disorders have complex genetic and environmental determinants. Studies of the pharmacogenetics of alcohol seek to identify variation in specific genes that interact with alcohol exposure to modify both the short-term and long-term effects of alcohol, including alcohol dependence. Given the difficulty in detecting differences related to genetic variation in complex genetic disorders such as alcohol dependence, it emphasizes the need to evaluate less complex phenotypes in association with alcoholism risk. There is evidence suggesting that genetically determined differences in alcohol sensitivity may represent one pathway by which an increase in alcohol dependence risk occurs. Alcohol exerts many of its effects via interactions with receptors for the major inhibitory amino acid gamma-aminobutyric acid (GABA). The actions of GABA are mediated by receptors belonging to two major classes, termed GABAA and GABAB. GABAA receptors are the most widely expressed in the central nervous system, and are involved in the reinforcing effects of alcohol. Because differences in sensitivity to alcohol are a risk factor for the development of alcohol use disorders, in the proposed protocol we conduct a genetic association study to investigate the effects of GABAA receptor subunit gene variation on the subjective, physiologic and neuroendocrine response to acute alcohol consumption in a healthy social-drinking population. Growth hormone (GH) secretion is among the neuroendocrine responses to acute alcohol administration to be examined during our study. It is well known that GH is synthesized and secreted from the anterior pituitary gland in a pulsatile manner throughout the day; between the peaks, basal GH levels are low, often undetectable by our current assay methods. Therefore, we plan to evaluate GH secretion following the administration of GH secretagogues. We propose to administer arginine, which is widely used in humans for stimulation of GH secretion upon its administration. These stimulation tests will also be used to study the underlying mechanisms involved in alcohol¿s effects on growth-hormone release. In addition, given that the largest and most predictable of GH peaks occur about an hour after onset of sleep, we plan to examine neuroendocrine responses to acute alcohol administration during the night. Interestingly, one possible mechanism involved in alcohol effects on GH could be mediated by its effects on ghrelin. However, although a few studies have examined the effects of acute alcohol administration on ghrelin release, none of these studies examined the relationship between ghrelin and GH secretion following acute alcohol administration. Given that it is possible that the energy provided with alcohol administration rather than alcohol per se could account for the effects observed on ghrelin and GH secretion, we plan to examine neuroendocrine responses following administration of isocaloric, isovolemc beverages. SIGNIFICANCE My proposed studies will expand our understanding of one possible mechanism by which risk of alcoholism may be transmitted. The present study will include a detailed examination of gene variations in relationship to both changes in validated subjective measures of alcohol¿s effects and quantitative behaviorally relevant measures of alcohol¿s effects on neural processing. In addition, the present protocol will examine the underlying mechanisms involved in alcohol¿s effects on neuroendocrine measures. Furthermore, this proposal will extend these findings by examining if genetic variations that are found to predict differences in response to alcohol will also predict genetic risk for alcohol dependence. The current proposal is innovative, because although it employs many of the same assessments (subjective alcohol effects rating scales, physiological measures) and alcohol dosing methods that have been refined in human laboratory studies of alcohol, it focuses on the role of genetic variation in receptors involved in alcohol¿s action and the mechanisms involved in alcohol¿s effects on neuroendocrine measures. Ultimately, greater understanding of the role of genetic variation and the mechanisms mediating alcohol effects in humans may contribute to the development of pharmacogenetic and other interventional approaches in the screening and management of alcohol dependence. SUBJECT POPULATION Healthy male and female subjects 21 to 30 years old will be recruited via newspaper, flyers and other advertisements from the local Los Angeles area and on surrounding college/university campuses. Subjects will be recruited to yield a broadly representative sample of community-dwelling young adult drinkers. All interested persons will be screened by telephone using a questionnaire addressing demography, personal and familial alcohol and drug use patterns and associated problems, and medical and mental health history. This telephone screening will address major study inclusion and exclusion criteria, and identify at the outset the majority of those who do not qualify. Following the initial telephone screening, eligible individuals will be interviewed in person by an interviewer with experience in administering structured diagnostic interviews. Prior to any research participation, subjects will be required to provide written informed consent using a form approved by the Cedars-Sinai Institutional Review Board.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 该协议代表了 NIH K23 指导的以患者为导向的研究职业发展奖的目标。根据该协议，受试者将参与对急性酒精给药的急性主观、生理和神经内分泌反应的全面表征。 该协议将实现以下具体目标： 1. 检查 GABAA 受体亚基基因的遗传变异是否部分介导了健康社交饮酒人群中观察到的酒精敏感性差异。 2. 检查健康社交饮酒人群对急性饮酒的生理、主观和神经内分泌反应。 基本原理 酒精依赖是一种非常普遍的疾病，与严重的发病率和死亡率相关，据估计，美国大约 14% 的男性和 5% 的女性在一生中的某个时候会经历酒精滥用或酒精依赖的症状。明确的证据表明，酒精使用障碍具有复杂的遗传和环境决定因素。对酒精的药物遗传学的研究旨在识别与酒精暴露相互作用的特定基因的变异，以改变酒精的短期和长期影响，包括酒精依赖。 鉴于难以检测与酒精依赖等复杂遗传性疾病的遗传变异相关的差异，因此强调需要评估与酗酒风险相关的不太复杂的表型。有证据表明，遗传决定的酒精敏感性差异可能代表了一种途径。这会增加酒精依赖的风险。 酒精通过与主要抑制性氨基酸 γ-氨基丁酸 (GABA) 受体相互作用来发挥其多种作用。GABA 的作用由属于两大类的受体介导，即 GABAA 和 GABAA 受体，它们是表达最广泛的受体。由于对酒精敏感性的差异是发生酒精使用障碍的危险因素，因此在拟议的方案中，我们进行了一项遗传关联研究，以了解酒精的作用。研究 GABAA 受体亚基基因变异对健康社交饮酒人群对急性饮酒的主观、生理和神经内分泌反应的影响。 生长激素（GH）的分泌是我们研究期间要检查的神经内分泌反应之一，众所周知，GH 在一天中的高峰期和基础期之间以脉动方式从垂体前叶合成和分泌。 GH 水平较低，通常无法通过我们目前的检测方法检测到，因此，我们计划在施用 GH 促分泌素后评估 GH 分泌，精氨酸广泛用于人体刺激。这些刺激测试也将用于研究酒精所涉及的潜在机制。此外，考虑到最大且最可预测的 GH 峰值出现在入睡后约一小时，我们计划检查夜间急性饮酒后的神经内分泌反应。 目前尚不清楚，酒精对 GH 的影响的一种可能机制可能是通过其对 ghrelin 的影响来介导的。然而，尽管有一些研究研究了急性饮酒对 ghrelin 释放的影响，但这些研究都没有研究 ghrelin 和 GH 分泌之间的关系。鉴于有可能是酒精摄入所提供的能量而不是酒精本身可以解释观察到的对生长素释放肽和生长激素分泌的影响，我们计划检查服用酒精后的神经内分泌反应。等热量、等体积饮料。 意义 我提出的研究将扩大我们对酗酒风险传播的一种可能机制的理解，本研究将包括对与经过验证的主观酒精测量值的变化相关的基因变异的详细检查。酒精的影响和定量行为相关措施¿此外，本协议将检查酒精涉及的潜在机制。此外，该提案将通过检查预测酒精反应差异的遗传变异是否也可以预测酒精依赖的遗传风险来扩展这些发现。与人类酒精实验室研究中改进的相同评估（主观酒精影响评级量表、生理测量）和酒精剂量方法相同，它重点关注与酒精有关的受体中遗传变异的作用。酒精的作用和机制¿最终，更好地了解遗传变异的作用和调节人类酒精影响的机制可能有助于开发药物遗传学和其他干预方法来筛查和管理酒精依赖。 受试者群体 将通过报纸、传单和其他广告从洛杉矶当地地区和周边学院/大学校园招募 21 至 30 岁的健康男性和女性受试者，以产生具有广泛代表性的社区年轻人样本。所有感兴趣的人都将通过电话筛查，使用问卷调查人口统计、个人和家庭酒精和药物使用模式及相关问题，以及医疗和心理健康史。该电话筛查将解决主要研究的纳入和排除标准，并确定。一开始，大多数人都不符合资格。 初步电话筛选后，符合条件的个人将接受具有结构化诊断访谈管理经验的访谈员的亲自访谈，在参与任何研究之前，受试者需要使用经 Cedars-Sinai 机构审查批准的表格提供书面知情同意书。木板。