A History of Chronic Repeated Predation Stress Reduces Aversion to Ethanol Adulteration in Male, but not Female, C57Bl/6J Mice

Background: Trauma related psychiatric disorders, such as posttraumatic stress disorder (PTSD), and alcohol use disorder (AUD) are highly comorbid illnesses that separately present an opposing, sex-specific pattern, with increased prevalence of PTSD in females and increased prevalence of AUD diagnoses in males. Likewise, PTSD is a risk factor in the development of AUD, with conflicting data on the impact of sex in the comorbid development of both disorders. Because the likelihood of experiencing more than one traumatic event is high, we aim to utilize chronic exposure to adolescent and early adult predator stress to query the extent to which sex interacts with chronic stress to influence alcohol consumption, or cessation of consumption. Methods: Male (n=16) and female (n=15) C57BL/6J mice underwent chronic repeated predatory stress (CRPS) or daily handling for two weeks during adolescence (P35-P49) and two weeks during adulthood (P65-P79). All mice were subject to open field testing and marble burying analysis as metrics of anxiety-like behavior. Mice subsequently underwent a two-bottle choice intermittent ethanol access (IEA) phase (P90-131) with the options of 20% ethanol or water. After establishing drinking behavior, increasing concentrations of quinine were added to the ethanol to assess ethanol seeking behavior in the presence of an aversive stimuli, as a metric of compulsive-like drinking. Results: CRPS increased baseline corticosterone and anxiety-like behaviors in the open field in both male and female mice as compared to control mice that had not been exposed to CRPS. Consistent with previous reports, we observed a sex difference in alcohol consumption such that females consumed more ethanol per gram of body mass than males. In addition, CRPS increased both alcohol intake by weight and preference, suggesting compulsive-like drinking behavior in male mice during quinine adulteration. Conclusion: Collectively, we demonstrate that CRPS during late adolescence and early adulthood can induce anxiety-like behavior in both sexes but selectively influences ethanol intake in males. Male mice with a history of CRPS continue to engage in ethanol seeking behaviors despite being paired with an aversive gustatory stimulus, suggesting dependence-like drinking behavior. Our results suggest that stress may play a role in the development of anxiety-like behaviors and also drive a sex-specific alteration in drinking behavior.