More women are being diagnosed with alcohol use disorder (AUD), are increasing the amount of alcohol they are drinking, and are partaking in risky drinking behaviors. Compulsive drinking which persists despite negative consequences is a hallmark of AUD. Preclinical aversion‐resistant models suggest that females may be more vulnerable to the rewarding effects of alcohol such that they show increased compulsivity when drinking is punished with quinine, a bitter tastant.

Male and female C57BL/6J mice were trained in an operant response task on a first‐order fixed ratio schedule. Experiment 1 tested responding for escalating concentrations (10 to 25%) of ethanol (EtOH). Experiment 2 assessed the effects of increasing concentrations of quinine (100, 250, or 500 μM) on responding for 10% EtOH followed by a 48‐hour 2‐bottle choice quinine preference test. Experiment 3 investigated the effects of increasing concentrations of quinine (100, 250, or 500 μM) on responding for 2.5% sucrose.

Experiment 1 revealed that females respond more than males for 15% EtOH. Experiment 2 showed that females tolerate higher concentrations of quinine in EtOH than males. Males reduced responding for 10% EtOH when adulterated with 250 or 500 µM of quinine, while females did not reduce responding at any concentration of quinine. Males and females also exhibited similar preference for quinine in a 2‐bottle drinking task. Experiment 3 demonstrated that both males and females reduced responding for 2.5% sucrose when quinine (100, 250, or 500 μM) was added.

Females respond more for EtOH at higher concentrations and continue to respond for 10% EtOH at all concentrations of quinine, suggesting that female mice are more motivated to respond for EtOH in an operant self‐administration paradigm than males. Understanding behavioral and mechanistic sex differences in responding for alcohol will allow for the advancement of treatments for women with AUD.