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-impaired driving is a major cause of motor vehicle accident and death in the United States. People who are arrested for DUI (Driving under the Influence) are at high risk to reoffend; approximately one in three of these individuals will commit another DUI offense in the three years following their first conviction (Nochajski & Stasiewicz, 2006). This high risk for recidivism in these individuals suggests that cognitive characteristics may contribute to a pattern of pathological decision making leading to impaired driving. Indeed, individuals with a history of DUI report higher rates of impulsiveness and behavioral dysregulation compared to their nonoffending peers. Relatively little research, however, has used laboratory methods to identify the specific behavioral characteristics, such as poor inhibitory control or heightened sensitivity to immediate reward, which may differentiate DUI offenders from nonoffenders. Further, little is known about how individuals with a history of DUI respond following an acute dose of alcohol. Study 1 examined impulsivity in 20 adults with a recent DUI conviction and 20 adults with no history of DUI using self-report and behavioral measures of impulsivity. This study also used a novel decision-making paradigm to examine how different levels of risk and reward influenced the decision to drive after drinking in both groups. Results of this study found that DUI offenders did not differ from controls in their performance on behavioral measures of impulsivity. They did, however, report higher levels of impulsivity and demonstrated a greater willingness to tolerate higher levels of risk for more modest rewards. Study 2 examined the acute effects of alcohol and expectancy manipulation on driving performance and decision making in the same group of participants. Neither alcohol nor expectancy manipulation exerted a systematic effect on decision making in either group. Alcohol impaired driving performance equally in both groups, but the DUI group perceived themselves as less impaired by alcohol. Expectancy manipulation eliminated this group difference in perceived driving ability. Taken together, these findings identify processes that risk of impaired driving in DUI offenders. They may perceive themselves as less impaired by alcohol, leading to risky decision making when drinking. Expectancy manipulation may be a viable method of reducing risky decision making in DUI offenders.

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.