Pharmacogenetics of Alcohol: Treatment Implications

酒精的药物遗传学：治疗意义

• 批准号: 7034069
• 负责人: JONATHAN M COVAULT
• 金额: $ 42.77万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034069
• 关键词: GABA receptor; alcoholic beverage consumption; alcoholism /alcohol abuse; ataxia; breath tests; clinical research; clinical trials; desoxycorticosterone; drug addiction; gas chromatography mass spectrometry; genetic susceptibility; genotype; human subject; interview; neuropharmacology; opioid receptor; oxidoreductase inhibitor; patient oriented research; pharmacogenetics; pharmacokinetics; pregnanolone; questionnaires; single nucleotide polymorphism; testosterone 5 alpha reductase

DESCRIPTION (provided by applicant): Studies of the genetic basis of alcohol's effects and their modification by pharmacological agents represent a promising approach to the development of medications to treat problem drinking and alcohol dependence. This proposal employs a human laboratory paradigm to study the moderating effect of genetic variation of GABRA2, which encodes the GABAA-receptor alpha-2 subunit and GABAergic neuroactive steroids on subjective and physiological effects of alcohol when consumed by light drinkers compared with heavy drinkers. This study will explore the hypothesis that effects of alcohol are in part mediated by increased production of neuroactive steroids, which interact with GABAA-receptors. We propose to study non-dependent drinkers using a 4-session within- subjects design in which alcohol / placebo is paired with dutasteride / placebo pretreatment. Dutasteride is a 5-alpha steroid reductase (5AR) inhibitor that limits the production of dihydrotestosterone and the 5alpha-reduced neuroactive steroids allopregnanolone, pregnanolone and 3alpha, 5alpha-THDOC. This work continues our pilot studies in this area in which we demonstrated that both an alcohol-dependence associated GABRA2 allele and inhibition of 5AR reduce the subjective response to alcohol. We will extend work in this area by 1) examining a larger group of subjects that includes both light and heavy drinkers balanced on GABRA2 genotype, 2) include objective measures of alcohol's effects, 3) measure plasma concentrations of neuroactive steroids and their adrenal steroid hormone precursors at several time points following alcohol, 4) examine effects of a more potent and specific inhibitor of 5alpha-reductase (to validate and clarify the relationship of neuroactive steroids to alcohol effects), and 5) examine the effects of polymorphisms in steroid 5alpha-reductase and mu-opioid receptor genes on alcohol-induced neuroactive steroid elevations and behavioral responses. To conduct this work, we have developed collaborations among several investigators with expertise in human alcohol challenge studies and the physiological effects of alcohol, genetics, and steroid hormone analysis, and will make use of an NIH-funded GCRC to augment resources. This study provides a foundation for translating pre-clinical findings on neuroactive steroids to the development of medications to treat alcohol use disorders. Public information description: Alcohol abuse and dependence remain important public health problems. Inherited (e.g. genetic) risk factors are thought to be important in the development of alcohol use problems. This proposal employs a human laboratory paradigm to study the moderating effect of genetic variation in several candidate genes and the role of alcohol induced neuroactive steroids on subjective and physiological effects of alcohol when consumed by light drinkers compared with heavy drinkers.

描述（由申请人提供）：对酒精作用的遗传基础及其药物调节的研究代表了开发治疗饮酒问题和酒精依赖的药物的一种有前途的方法。该提案采用人类实验室范例来研究 GABRA2 遗传变异的调节作用，GABRA2 编码 GABAA 受体 α-2 亚基和 GABA 能神经活性类固醇，与大量饮酒者相比，轻度饮酒者饮酒时对酒精的主观和生理影响。这项研究将探讨这样的假设：酒精的影响部分是由神经活性类固醇的产生增加介导的，这些类固醇与 GABAA 受体相互作用。我们建议使用 4 个疗程的受试者内设计来研究非依赖性饮酒者，其中酒精/安慰剂与度他雄胺/安慰剂预处理配对。度他雄胺是一种 5-α 类固醇还原酶 (5AR) 抑制剂，可限制二氢睾酮和 5α 还原神经活性类固醇四氢孕酮、孕酮和 3α、5α-THDOC 的产生。这项工作是我们在该领域的试点研究的延续，其中我们证明了与酒精依赖相关的 GABRA2 等位基因和 5AR 的抑制都会降低对酒精的主观反应。我们将通过以下方式扩展这一领域的工作：1) 检查更大的受试者组，其中包括 GABRA2 基因型平衡的轻度和重度饮酒者，2) 包括酒精影响的客观测量，3) 测量神经活性类固醇及其肾上腺类固醇激素的血浆浓度酒精后几个时间点的前体，4) 检查更有效和更特异性的 5α-还原酶抑制剂的作用（以验证和澄清神经活性类固醇与酒精作用的关系），以及5) 检查类固醇5α-还原酶和μ-阿片受体基因的多态性对酒精诱导的神经活性类固醇升高和行为反应的影响。为了开展这项工作，我们在人类酒精挑战研究以及酒精的生理影响、遗传学和类固醇激素分析方面具有专业知识的几位研究人员之间建立了合作，并将利用 NIH 资助的 GCRC 来增加资源。这项研究为将神经活性类固醇的临床前发现转化为治疗酒精使用障碍的药物开发奠定了基础。公开信息说明：酒精滥用和依赖仍然是重要的公共卫生问题。遗传（例如遗传）风险因素被认为在酒精使用问题的发展中很重要。该提案采用人类实验室范式来研究几个候选基因中遗传变异的调节作用，以及与大量饮酒者相比，轻度饮酒者饮酒时酒精诱导的神经活性类固醇对酒精的主观和生理影响的作用。