Subjective and Physiological Effects of Alcohol: Role of Genetic Variation and Adrenal Hormones

Description:
Alcohol has multiple pharmacological effects, though which of these effects relate to the risk of alcohol dependence is not clear. Family-based and case-control genetic studies of alcohol dependence indicate that genetic variations of the adjacent GABAA g1- and a2-subunit genes, GABRG1 and GABRA2, influence the risk of developing alcohol dependence. Preliminary results from our alcohol laboratory studies in humans suggest that variation in GABRA2 influences the subjective effects of alcohol. Animal studies indicate that the neuroactive steroid allopregnanolone is an alcohol-modulated endogenous agonist at GABAA receptors and that genetic variation in steroid 5a-reductase type I gene which generates neuroactive steroids, may moderate alcohol effects. Studies in humans have identified a functional m-opioid receptor polymorphism (Asn40Asp) that moderates the feedback regulation of the HPA axis and may be associated with variation in the neurosteroid response to acute alcohol. To better define the role of GABRA2 gene variation, neuroactive steroids and genetic variants of 5a-reductase and m-opioid receptor genes on the acute effects of alcohol in humans, we propose to conduct a laboratory study of non-alcohol dependent drinkers using a 4-session design in which alcohol/placebo beverage is paired with dutasteride/placebo pretreatment. Dutasteride, an inhibitor of both type I and type II 5a-reductase enzymes, blocks the production of 5a-reduced neuroactive steroids. This study will extend our preliminary findings with finasteride by including a) a placebo control for alcohol, b) a more specific inhibitor of both 5a-reductase isoenzymes, c) a larger group of subjects (including both light and heavy drinkers), d) quantitative tests of static ataxia and response inhibition, e) plasma concentrations of neuroactive steroids and their adrenal steroid hormone precursors at several time points following alcohol administration, and f) the effects of polymorphisms in steroid 5a-reductase enzymes and m-opioid receptor genes on acute alcohol effects (including changes in levels of neuroactive steroids).