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; 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的研究及其对药理剂的修饰是一种有前途的方法来开发治疗问题饮酒和酒精依赖性的药物。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，该遗传变异编码GABAA受体alpha-2亚基和GABA能神经活性类固醇对饮酒时饮酒时对酒精的主观和生理影响的GABA能神经活性。这项研究将探讨以下假设：酒精的作用部分是由与GABAA受体相互作用的神经活性类固醇产生增加所介导的。我们建议使用4条饮酒者使用4条饮酒者在主题内设计，其中酒精 /安慰剂与Dutasteride /安慰剂预处理配对。 Dutasteride是一种5-α类固醇还原酶（5AR）抑制剂，可限制二氢睾丸激素的产生和5Alpha还原的神经活性类固醇adlopregnanolone，Phindanolone，孕妇和3alpha，5alpha-Thdoc。这项工作继续我们在该领域的试点研究，我们证明了酒精依赖性相关的Gabra2等位基因和对5AR的抑制降低了对酒精的主观反应。我们将在该领域的工作扩展1）检查一组较大的受试者，其中包括在Gabra2基因型上保持平衡的光和重饮酒者，2）包括客观的酒精效应的客观测量，3）测量神经活性类固醇类固醇及其肾上腺固醇激素的血浆浓度及其肾上腺类固醇激素前体在酒精后的几个时间点和素养的效果，4）均与5级的相关效果（4）相关的效果（4）神经活性类固醇对酒精作用）和5）检查多态性在类固醇5alpha-还原酶和Mu-阿片受体基因对酒精诱导的神经活性类固醇高度和行为反应的影响。为了进行这项工作，我们已经开发了几位研究人员的合作，在人类酒精挑战研究方面具有专业知识以及酒精，遗传学和类固醇激素分析的生理影响，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结果转化为治疗酒精使用障碍的药物的发展提供了基础。公共信息描述：酗酒和依赖仍然重要的公共卫生问题。遗传（例如遗传）危险因素被认为对饮酒问题的发展很重要。该提案采用人类实验室范例来研究几种候选基因遗传变异的调节作用，以及与饮酒者相比，酒精饮用者消耗饮酒时，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。