Ethanol preference is impacted by estrus stage but not housing or stress in female C57BL/6J mice

Vulnerability to maladaptive patterns of alcohol use, including dependence and relapse, is influenced by a combination of biological and environmental factors. A better understanding of how individual factors influence alcohol use is needed to help reduce alcohol dependence and relapse rates in the general population. This study explored how environmental enrichment (EE), stress and estrus cycle stage affect ethanol (ETOH) preference in female mice. Mice were housed in enriched or standard environments and exposed chronically to ETOH for two hours a day for twelve days, before entering a brief ETOH-free abstinence period. At the end of this abstinence period, mice were exposed to a series of mild stressors (forced swim tests) and anxiety was assessed via an elevated plus-maze. Preference was measured using a two-bottle choice test prior to ETOH exposure (baseline), after chronic ETOH exposure, and immediately following the abstinence period and stressor. Results revealed that mice preferred ETOH more strongly after chronic ETOH exposure, but that this increase was not affected by environment. ETOH preference was further increased after a brief abstinence period, but preference was not affected by environment or mild stress. However, mice in the proestrus/estrus stage of the estrus cycle preferred ETOH more strongly after a brief abstinence period than did mice in the metestrus/diestrus stage, suggesting that circulating levels of gonadal hormones may contribute to the incubation of drug preference. Anxiety- and despair-like behaviors were not impacted by estrus cycle stage. These findings suggest that estrus stage may affect ETOH preference, even after relatively short drug-free periods. Further research is needed to rectify the role of EE and stress in individual vulnerability or resilience to substance abuse. These findings also highlight a need for increased research into how gonadal hormones may influence ETOH preference in both mice and humans