| Alcohol dependence (AD) is a complex disease for which a complete understanding of its etiology is lacking and existing therapies are only partially effective. Recent preclinical evidence has implicated neuroactive steroids as mediators some of the effects of alcohol, however, study of these endogenous hormones in the effects of alcohol in humans and in animal models of adolescent alcohol exposure is limited. We examined naturally occurring variation in human genes for neurosteroid metabolism in a case-control sample of alcoholics, reports of subjective effects of alcohol in social drinkers in response to alcohol, and a model of adolescent alcohol exposure to study the potential role of neuroactive steroids in the effects of alcohol and the risk for development of AD. We found that genetic variations in two neuroactive steroid synthetic enzyme genes [encoding 5a-reductase type 1 and 3a-hydroxysteroid dehydrogenase type 2 (3a-HSD)] were associated with AD, such that the minor allele for each marker was more common in controls than in alcoholics. In a human laboratory study of alcohol administration we found that the AD risk allele of the non-synonymous polymorphism in the gene encoding 3-HSD Type 2 (aka 17beta-reductase Type 5), was associated with decreased subjective effects of alcohol and a decreased conversion of androsterone to androstanediol, a potent GABAA receptor modulating neuroactive steroid. Finally, we found that nightly exposure to oral alcohol for 7 days in male rats during late adolescence, an age characterized by rapid increases in neuroactive steroids, resulted in a 4-fold increase in alcohol preference 30 days later in adulthood. These findings contribute to our understanding of the role of neuroactive steroids as mediators of the effects of alcohol in humans and during adolescent alcohol exposure. |
