Clarifying the mechanisms by which alcohol affects the human brain and behavior could yield new pharmacological targets for treating alcohol-related disorders. Among the most exciting pre-clinical advances in understanding alcohol effects has been the discovery of the role of """"""""neurosteroids' in modulating GGGABA-A receptor sensitivity to alcohol. Remarkably, no studies (to our knowledge) have examined alcohol-neurosteroid-GABA interactions in humans, and none has assessed the ability of neurosteroid manipulation to antagonize alcohol's effects. We will determine if circulating baseline neurosteroid and GABA levels, as well as alcohol induced changes in these levels, predict behavioral responses to alcohol in healthy male and female controls. To test the mechanism and principle of pharmacologic neurosteroid blockade of alcohol intoxication (as has been shown in animals), we will also examine the ability of pregnenolone (a GABA-A receptor antagonist neurosteroid) to block the acute intoxicating effects of alcohol. One hundred normal controls (50 men and 50 women) will be treated in a double-blind manner with pregnenolone or placebo and subsequently administered alcohol or placebo. Thus, on four separate test days (aside from an initial practice/acclimation day), each subject will receive, in a randomized, double-blind, counter-balanced manner, each of the following sequences: 1) placebo + placebo, 2) placebo + alcohol, 3) pregnenolone + placebo, and 4) pregnenolone + alcohol. Behavioral measures and blood for neurosteroid and GABA assays will be collected at baseline and following drug administration. These data will clarify alcohol's mechanism of action in humans and the underpinnings of individual differences in alcohol sensitivity. They will also provide normative data with which to compare subsequent data in individuals with (or at risk for) alcoholism, may lead to better biological sub-typing of patients with alcohol disorders and may foster the development of novel, mechanism-based treatments for acute alcohol intoxication, alcoholism, alcohol tolerance and alcohol withdrawal.
