Although multiple targets for ethanol in the mammalian nervous system have been proposed, the effects of ethanol that bring about alterations in behavior are not understood. We have taken a genetic approach to test suspected targets of ethanol and identify new targets and pathways that can be affected by ethanol to produce behavioral changes in C. elegans with a focus on the behavior of locomotion. Examination of existing nervous system mutants suggests that regulators of synaptic transmission play a role in sensitivity to ethanol in C. elegans . Our genetic screens for new mutations that alter the sensitivity to ethanol have identified multiple mutations in the calcium-activated potassium channel encoded by the slo-1 gene. Loss of function mutations in slo-1 result in ethanol resistance. We can restore wild-type ethanol sensitivity to slo-1 mutant animals by expressing slo-1 only in neurons but not by expressing slo-1 only in muscle (many thanks to Mike Nonet for the slo-1 constructs). Our data suggests that SLO-1 is likely to represent a target of ethanol in the nervous system of C. elegans and may be a conserved target of ethanol in mammals (Dopico et al . 1999 Neurochem. Int. 35:103-106). We have also shown that C. elegans displays acute tolerance, the process by which animals adapt from an intoxicated state to a sober state during a single, maintained and prolonged exposure to ethanol. During mapping experiments we noticed that the Hawaiian-isolated wild-type strain CB4856 shows rapid acute tolerance compared with the N2 strain after both strains show a similar level of initial intoxication. de Bono and Bargmann (1998 Cell 94:679-689) identified an allelic variant at the npr-1 locus in social strains, including CB4856. We found that other loss of function alleles of npr-1 display rapid acute tolerance and that the rapid tolerance in CB4856 could be mapped to the region of the npr-1 gene. These data suggest that npr-1 may function to limit the rate of acute tolerance. de Bono and Bargmann showed that npr-1 encodes a neuropeptide Y (NPY) receptor-like molecule so it is of significant interest to us that variation in NPY levels in mammals can alter ethanol sensitivity and tolerance (Thiele et al . 1998 Nature 396:366-369).