The upstream analysis performed with IPA looks for endogenous genes and molecules that could be responsible for the alterations in gene expression, and also for drugs that could have similar or opposing effects. Negative z-scores in Supplementary Table 3 mean that the molecule causes expression of the subset of genes it regulates to go in the opposite direction to those caused by the ethanol exposure. The drugs that have negative z-scores (Table 5) might, therefore, reverse some of the effects of this repeated high level of alcohol exposure. Many of these are drugs already have FDA approval for another indication. One of them, mifepristone, is in early clinical trials (Vendruscolo et al., 2015); early indications are that it may decrease alcohol seeking in alcohol dependent individuals. PPARα agonists (fibrates and thiozolidinediones) have already been used in pre-clinical studies and shown to reduce ethanol intake in mice (Blednov et al., 2015). Isoquercitrin, which is found in medicinal herbs like St. John’s Wort, appears to increase the expression of many genes in the cholesterol pathway (Soundararajan et al., 2008) that were decreased
