Alcohol use disorder is a global health issue that affects a significant portion of the population, with affects including both negative mental and physical consequences. Currently, there are few treatment options available to those who suffer from alcohol use disorder, alcohol abuse, or alcohol dependence. Identifying candidate genes or environmental influences would therefore improve the means for possible treatments or identification of those people at risk for alcohol use disorder. Previous studies in humans have demonstrated an inverse association between initial sensitivity and risk for alcohol abuse. This connection allows investigators, and our laboratory, to investigate genetic and environmental factors that may influence initial ethanol sedation. Our laboratory utilizes Drosophila melanogaster (flies) as a model organism to identify these such factors influencing acute behavioral responses to alcohol. Our lab has found evidence for both environmental and genetic factors that influence initial alcohol sensitivity in flies. In one study, flies that are fed increased amounts of dietary yeast are resistant to ethanol. We have found that this ethanol resistance is related to the amount of nutrients that is consumed, which then affects alcohol uptake/metabolism, to influence initial alcohol sensitivity. Importantly, we found that serotonergic neuron function is essential for regulating the consumption of high dietary yeast media for the increased nutrient intake to occur. In two separate projects, we identified a role for myocyte enhancer factor 2 (Mef2) and nitric oxide synthase (Nos) in initial alcohol sensitivity. Mef2 was obtained via a GWAS study identifying genes with an association with initial sensitivity in humans. We found that decreasing or altering Mef2 expression, using mutants or Mef2 RNAi, resulted in flies having decreased sensitivity to alcohol. The gene Nos, came out of a previous genetic interaction screen in the laboratory. Multiple reagents to assess Nos’s role in alcohol behavior were obtained and consistent evidence from three piggyBac transposon insertion flies and, importantly, a Nos null fly, demonstrate that decreased Nos expression results in increased ethanol sensitivity. Other preliminary results suggest that Nos expression during adulthood, as well as the mechanism of S-nitrosation, may be important for ethanol sedation in Drosophila.