Sex and Genetic Differences in Behavioral Engagement of Crossed High Alcohol‐Preferring and Low Alcohol‐Preferring Mice

Abstract

Excessive levels of alcohol consumption play a major role in numerous alcohol-related harms, including a heightened risk of developing problematic drinking behaviors. Those who develop alcohol use disorder (AUD) often struggle with persistent difficulties in controlling their drinking, experience withdrawal symptoms, and engage in risky behaviors that pose danger to themselves and others. Advances in treating AUD may be supported by identifying specific cognitive and emotional factors that drive excessive alcohol consumption. Recognizing reliable behavioral biomarkers is instrumental in assessing the risk of developing alcohol problems and preventative care strategies. This study investigates innate behavioral differences associated with genetic predisposition for alcohol use by comparing crossed high alcohol-preferring (cHAP) and low alcohol-preferring (LAP) mice. Since there have been links between heightened impulsivity and excessive alcohol use, we hypothesized that cHAP mice would exhibit higher levels of impulsivity compared to LAPs. No significant differences were found in impulsivity between the mouse lines or sexes. cHAPs adapted to shorter stimulus durations (SDs), whereas LAPs showed a marked decline in correct responses and an increase in omission rates as task difficulty increased. Significant sex differences within the cHAP line were found, with females demonstrating higher accuracy, lower correct latency, and increased perseveration. This behavior points to potential sex-specific neural activation in cognitive processing areas. Future studies should explore salient brain regions to understand their roles in behavioral regulation and sex-specific responses to challenges. This study provides a foundation for exploring the interaction of genetic predisposition, sex differences, and neural mechanisms in alcohol preference and behavior.