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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 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，受试者将参与急性主观，物理和神经内分泌对急性酒精给药的全面表征。 该协议将实现以下特定目标： 1。检查GABAA - 受体亚基基因的遗传变异是否介导了健康的社会饮食人群中观察到的对酒精敏感性的差异。 2。检查健康饮酒人群中对急性酒精给药的身体，主观和神经内分泌的反应。 理由 酒精依赖性是一种高度普遍的疾病，与严重的发病率和死亡率有关。据估计，在美国，大约14％的男性和5％的女性将经历酗酒或生活中依赖的症状。有明确的证据表明，酒精使用障碍具有复杂的遗传和环境决定者。对酒精的药物遗传学的研究旨在确定特定基因与酒精相互作用的变异，以改变酒精的短期和长期影响，包括酒精依赖。 鉴于难以检测与诸如酒精依赖性复杂遗传疾病的遗传变异有关的差异，因此它强调了与酒精中毒风险相关的评估不太复杂的表型的必要性。有证据表明，酒精敏感性的遗传确定的差异可能代表了一种途径，而酒精依赖风险的增加。 酒精通过与主要抑制性氨基酸γ-氨基丁酸（GABA）的受体相互作用来执行许多作用。 GABA的作用是由属于两个主要类别的受体介导的，称为GABAA和GABAB。 GABAA受体是中枢神经系统中最广泛表达的，并且参与了酒精的增强作用。由于对酒精的敏感性的差异是饮酒障碍发展的危险因素，因此在拟议的方案中，我们进行了一项遗传关联研究，以研究GABAA受体亚基基因基因变异对健康社交饮酒人群中主观，生理和神经内分泌反应对急性酒精消耗的主观，生理和神经内分泌反应的影响。 生长马（GH）分泌是在我们的研究期间对急性酒精给药的神经内分泌反应之一。众所周知，GH全天以搏动方式从垂体前腺体合成并分泌。在峰之间，基本的GH水平很低，通常无法通过我们当前的测定方法检测到。因此，我们计划评估GH促进aggus的管理后的GH分泌。我们建议给予精氨酸，该精氨酸在人体中广泛用于刺激GH的分泌。这些刺激测试还将用于研究与酒精对生长激素释放的影响有关的潜在机制。此外，鉴于GH峰的最大，最可预测的是在睡眠发作后约一个小时发生，我们计划检查夜晚对急性酒精给药的神经内分泌反应。 有趣的是，酒精对GH涉及的一种可能的机制可能是由于其对生长素释放蛋白的作用而介导的。但是，尽管一些研究检查了急性酒精给药对生长素释放的影响，但这些研究都没有研究急性酒精给药后生长素和GH分泌之间的关系。鉴于饮酒而不是酒精本身提供的能量可能会解释对生长素释放和GH分泌的影响，因此我们计划检查等异含量，等元素弹药后的神经内分泌反应。 意义 我提出的研究将扩大我们对可能传播酗酒风险的一种可能机制的理解。本研究将包括详细研究与酒精效应的主观测量的变化以及酒精对神经加工的影响的验证主观测量的变化的基因变异。此外，本方案将检查与酒精对神经内分泌测量的影响有关的潜在机制。此外，该建议将通过检查发现可以预测对酒精反应差异的遗传变异是否还会预测酒精依赖的遗传风险，从而扩展这些发现。当前的提案具有创新性，因为它采用了许多相同的评估（主观酒精效应评级量表，物理措施）和酒精剂量方法，这些方法已在人类实验室研究中进行了完善，它的重点是遗传变异在酒精作用中所涉及的受体中的作用以及与酒精有关的机制涉及神经寄生的机制。最终，对遗传变异的作用以及介导酒精效应的机制的更深入了解可能有助于在筛查和管理酒精依赖性中的药物和其他介入方法的发展。 受试者人群 21至30岁的健康男性和女性受试者将通过报纸，传单和其他广告从当地洛杉矶地区以及周围的大学/大学校园招募。将招募受试者，以产生社区居住的年轻饮酒者的广泛代表性样本。所有感兴趣的人将使用电话调查表筛选，以解决销售障碍，个人和家庭酒精和吸毒模式以及相关问题以及医疗和心理健康史。该电话筛选将涉及主要的研究包含和排除标准，并从一开始就确定大多数没有资格的人。 在初始电话筛选之后，面试官将亲自面试符合条件的人，并具有管理结构化诊断访谈的经验。在进行任何研究参与之前，将要求受试者使用Cedars-Sinai机构审查委员会批准的表格提供书面知情同意书。