Alcohol abuse is a prevalent and serious disorder. Current drug treatments are inadequate, in part because the molecular nature of acute ethanol response is not well understood. A component of the ethanol response in humans that is predictive of the susceptibility to abuse alcohol is an individual’s naïve level of response to the drug [1], and this phenotype is strongly genetically influenced [2], [3]. This level of response to ethanol consists of at least two components, initial sensitivity and the development of acute functional tolerance (AFT). Initial sensitivity is measured during the onset of intoxication. In the nematode, C. elegans, we observe initial sensitivity at 10 minutes of ethanol exposure. AFT reflects a homeostatic mechanism of the nervous system to rapidly adapt to the intoxicating effects of ethanol that is not a result of ethanol metabolism. In mammals, AFT is observed during a single drug exposure and is measured as a greater behavioral impairment at the beginning of a drinking session than the impairment observed at a similar blood ethanol concentration during the falling phase of blood alcohol concentration. In
