Acute exposure to ethanol causes paralysis at high concentrations in the nematode Caenorhabditis elegans. We set out to elucidate the mechanism of the anesthetic action of ethanol by genetic approaches. We identified nine mutations that conferred reduced sensitivity to ethanol after chemical, irradiation, or transposon insertion mutagenesis. Of these nine, we further characterized five mutations that defined four genes, jud-1-jud-4. Analysis of the phenotypes of the animals heterozygous for two unlinked genes revealed that jud-1 and jud-3 act synergistically in a gene dose-dependent manner. We cloned jud-4 and found that it encodes a protein with limited homology to human Homer proteins. jud-4 was expressed in the hypodermis and vulva muscles, suggesting that this gene acts in tissues directly exposed to the external environment. Characterization of the other mutations identified in this study will facilitate the elucidation of the molecular mechanism for the anesthetic action of ethanol. (C) 2007 Elsevier Inc. All rights reserved.