Pharmacogenetics of Alcohol: Treatment Implications

描述(由申请人提供)：研究酒精作用的遗传基础及其被药理学试剂修饰，是开发治疗问题饮酒和酒精依赖药物的一种很有前途的方法。这项建议使用人类实验室范式来研究GABRA2基因变异的调节作用，GABRA2编码GABAA受体α-2亚单位和GABA能神经活性类固醇，与酗酒者相比，轻度饮酒者饮用酒精时，GABRA2基因变异对酒精的主观和生理影响具有调节作用。这项研究将探索这样一种假设，即酒精的作用部分是通过增加神经活性类固醇的产生来实现的，类固醇与GABAA受体相互作用。我们建议使用4次受试者内试验设计来研究非依赖型饮酒者，其中酒精/安慰剂与度他雄胺/安慰剂联合使用。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-还原的神经活性类固醇别孕酮、孕烯醇酮和3-α，5-THDOC的产生。这项工作继续了我们在这一领域的初步研究，我们证明了与酒精依赖相关的GABRA2等位基因和抑制5AR都减少了对酒精的主观反应。我们将通过以下方式扩展这一领域的工作：1)研究包括GABRA2基因平衡的轻度和重度饮酒者在内的更大范围的受试者；2)包括酒精影响的客观测量；3)测量酒精后几个时间点的神经活性类固醇及其肾上腺类固醇激素前体的浓度；4)检测更有效和特异的5α-还原酶抑制剂的效果(以验证和澄清神经活性类固醇与酒精效应的关系)；5)研究类固醇5α-还原酶和MU-阿片受体基因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。为了进行这项工作，我们在几个研究人员之间开展了合作，这些研究人员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，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提供了基础。公共信息描述：酗酒和依赖仍然是重要的公共卫生问题。遗传(如遗传)风险因素被认为在酒精使用问题的发展中起着重要作用。这项建议采用人类实验室范式来研究几个候选基因的遗传变异的缓和效应，以及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，当饮酒者与酗酒者相比时。

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.