Using animal models to identify genes and genetic pathways that influence ethanol-related behavior holds tremendous promise for providing mechanistic insight into the basic biology of alcohol abuse. Studies in animal models could lay the foundation for developing novel drug targets for treating alcohol abuse and for estimating risk of abusing alcohol in human populations. Starting with ethanol-responsive gene sets and other ethanol-related data from studies in mammals, we selected mammalian Clic4 as a candidate gene in ethanol behavior. Subsequent studies in multiple animal models directly linked the Clic family of genes to acute behavioral responses to alcohol. Partial loss of function in the sole Clic orthologue in Drosophila blunted the locomotor sedating effects of ethanol. In C. elegans, loss of function in the Clic orthologue exc-4 blunted ethanol sensitivity during the first few minutes of drug exposure, whereas loss of function in another Clic orthologue, exl-1, enhanced the development of acute functional tolerance to alcohol. Additionally, viral-mediated brain-specific overexpression of mammalian Clic4 decreased the sedating effects of high dose ethanol in mice. The ethanol behavior phenotypes were unrelated to altered
