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. ? ?
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