Ethanol Metabolism and Osmolarity Modify Behavioral Responses to Ethanol in C. elegans

Background Ethanol ( E t OH ) is metabolized by a 2‐step process in which alcohol dehydrogenase ( ADH ) oxidizes E t OH to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase ( ALDH ). Although variation in E t OH metabolism in humans strongly influences the propensity to chronically abuse alcohol, few data exist on the behavioral effects of altered E t OH metabolism. Here, we used the nematode Caenorhabditis elegans to directly examine how changes in E t OH metabolism alter behavioral responses to alcohol during an acute exposure. Additionally, we investigated E t OH solution osmolarity as a potential explanation for contrasting published data on C. elegans E t OH sensitivity. Methods We developed a gas chromatography assay and validated a spectrophotometric method to measure internal E t OH in E t OH ‐exposed worms. Further, we tested the effects of mutations in ADH and ALDH genes on E t OH tissue accumulation and behavioral sensitivity to the drug. Finally, we tested the effects of E t OH solution osmolarity on behavioral responses and tissue E t OH accumulation. Results Only a small amount of exogenously applied E t OH accumulated in the tissues of C. elegans and consequently their tissue concentrations were similar to those that intoxicate humans. Independent inactivation of an ADH ‐encoding gene ( sodh‐1 ) or an ALDH ‐encoding gene ( alh‐6 or alh‐13 ) increased the E t OH concentration in worms and caused hypersensitivity to the acute sedative effects of E t OH on locomotion. We also found that the sensitivity to the depressive effects of E t OH on locomotion is strongly influenced by the osmolarity of the exogenous E t OH solution. Conclusions Our results indicate that E t OH metabolism via ADH and ALDH has a statistically discernable but surprisingly minor influence on E t OH sedation and internal E t OH accumulation in worms. In contrast, the osmolarity of the medium in which E t OH is delivered to the animals has a more substantial effect on the observed sensitivity to E t OH .