Sensitivity to the initial rewarding effects of alcohol: Influence of age, sex, and β‐endorphin

Background Alcohol use disorders (AUDs) are widespread, devastating and complex. About 20% of people who consume alcohol develop problem use, accounting for over 5% of worldwide deaths. While numerous animal models have facilitated understanding of the consequences of excessive drinking, translational models allow for experimental manipulation of factors thought to contribute to AUD liability. Methods We employ a single‐exposure conditioned place preference assay (SE‐CPP) to investigate the influence of age, sex and the opioid peptide β‐endorphin (bE) on the initial rewarding effects of ethanol, a strong predictor of AUDs. Adolescent (PND28‐35) and adult (PND70‐90) male and female, control C57BL/6J and bE‐deficient mice were tested following a single injection of 1.5 g/kg of ethanol. Following the SE‐CPP test, animals were deeply anesthetized, sacrificed, and perfused, and the brains were subsequently sectioned at 40 microns and processed for immunohistochemical localization of c‐fos. One‐sample, two‐tailed t‐tests were used to assess drug preference or aversion and the locomotor effects of alcohol. Results In general, adults were more sensitive to the effects of alcohol than adolescents, and outcomes depended on sex and bE. For example, among females, adolescents were stimulated by the drug, but insensitive to locomotor effects as adults, while among males, adolescents were insensitive and adults sedated. Wild‐type adolescents of both sexes failed to evince initial subjective reward from the drug, but bE‐deficient adolescents, and all adult subjects, preferred a context once associated with ethanol over one that had been paired with saline. c‐fos immunoreactivity in multiple brain regions was attenuated in bE‐deficient animals, though influences of both sex and bE grew stronger with age. Conclusions This study demonstrates the utility of the SE‐CPP paradigm for elucidating factors that contribute to the liability for AUDs, and supports the growing body of research that shows that sensitivity to the rewarding effects of alcohol changes during the course of development. Our results also suggest that developmental contributions are sex‐dependent, and may also depend on the influence of endogenous opioid signaling. The initial subjective response to alcohol predicts subsequent alcohol misuse. We investigated developmental and genetic contributions to the reward from a single alcohol exposure using a modified conditioned place preference paradigm in mice. We f