Ethanol affects the formation of learning and memory in many species. However, the molecular mechanisms underlying the behavioral effects of ethanol are still poorly understood. In Caenorhabditis elegans, gustatory plasticity is a simple learning paradigm, in which animals after prolonged pre-exposure to a chemo-attractive salt in the absence of food show chemo-aversion to this salt during subsequent chemotaxis test stage. We characterized the effect of ethanol on this simple learning model. Our results showed that ethanol administration interfered with gustatory plasticity during pre-exposure or test stage in well-fed worms. Genetic analysis revealed that one mutant previously implicated involved in acute ethanol responses, slo-1, as well as two mutants with defects in serotonin synthesis, tph-1 and bas-1, failed to exhibit ethanol interference with gustatory plasticity. Furthermore, two metabotropic serotonin receptors, SER-4 and SER-7, were found to be involved in ethanol-mediated gustatory plasticity. In addition, the tph-1 and ser-4 loci were also involved in ethanol's effect on locomotion behavior. These data suggested an essential role of serotonin signaling in modulating acute effects of ethanol. © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society.