Alcohol abuse is a problem in our society. There are few treatments available, in part due to the unclear molecular mechanisms of ethanol’s effects. Human studies indicate that there is a genetic component influencing disease susceptibility, and that an individual’s initial response to alcohol can predict their development of addiction. We have taken a forward genetics approach to study one component of initial response, acute functional tolerance (AFT), in Caenorhabditis elegans. We identified bet11, a mutation that causes animals to be defective in the development of AFT. Genetic analysis suggested that the gene that bet11 disrupts participates in a synthetic genetic interaction with an unlinked natural allelic variant in another gene that alters ethanol response. We also examined the role of lipid membrane composition in the response to ethanol. Identification of modulators that are responsible for alcohol-induced responses will provide a greater understanding of the mechanisms that cause alcohol-related diseases.

Alcohol abuse and dependence are complex disorders that are influenced by many genetic and environmental factors. Acute behavioral responses to ethanol have predictive value for determining an individual’s long-term susceptibility to alcohol abuse and dependence. These behavioral responses are strongly influenced by genetics. Here, we have explored the role of genetic influences on acute behavioral responses to ethanol using the nematode worm, Caenorhabditis elegans. First, we explored the role of ethanol metabolism in acute behavior responses to ethanol. Natural variation in human ethanol metabolism machinery is one of the most reported and reproducible associations found to alter drinking behavior. Ethanol metabolism is conserved across phyla and alteration in this pathway alters acute behavioral responses to ethanol in humans, mice, rats, and flies. We have extended these findings to the worm and have shown that loss of either alcohol dehydrogenase or aldehyde dehydrogenase results in an increase in sensitivity to the acute effects of ethanol. Second, we explored the influence of differences in basal and ethanol-induced gene expression in ethanol responsive behaviors. We identified a set of candidate genes using the basal gene expression differences in npr-1(ky13) mutant animals to enrich for genes involved in AFT. This analysis revealed ethanol changes to the expression of genes involved in a variety of biological processes including lipid metabolism. We focused on a gene involved in the metabolism of fatty acids, acs-2. acs-2 encodes an acyl-CoA synthetase that activates fatty acids for mitochondrial beta-oxidation. Animals carrying mutant acs-2 have significantly reduced AFT and we explored the role of genes in the mitochondria beta-oxidation pathway for alterations in ethanol responsive behaviors. We have shown that knockdown of ech-6, an enoyl-CoA hydratase, enhances the development of AFT. This work has uncovered a role for fatty acid utilization pathways in acute ethanol responses and we suggest that natural variation in these pathways in humans may impact the acute alcohol responses to alcohol that in turn influence susceptibility to alcohol abuse and dependence.