Winder, D. | bioRxiv Science

bioRxiv2025

Adolescent onset of volitional ethanol intake normalizes sex differences observed with adult-onset ethanol intake and negative affective behaviors during protracted forced abstinence

RationaleNegative affect during ethanol abstinence can lead to relapse and dependence. Voluntary ethanol drinking models are crucial for examining negative affect following chronic ethanol access, but female rodents often drink more ethanol than males, complicating comparisons between sexes. Since chronic adolescent ethanol use poses a substantial risk for later alcohol use disorder, we hypothesize that adolescence is a critical window for consolidating drinking behavior before major hormonal changes affect ethanol consumption. ObjectivesThis study compared sex differences in voluntary ethanol consumption and negative affective behavior in mice that initiated ethanol consumption during early adolescence ([~]PND30) or early adulthood (>PND49). MethodsMale and female C57BL/6J mice underwent the Chronic Drinking Forced Abstinence (CDFA) paradigm, with the "Ethanol" group given two-bottle choice access to ethanol and water, and the "Water" group given two water bottles. Ethanol intake and preference were measured over six weeks. Two weeks following ethanol removal, mice underwent behavioral testing for negative affective-like behavior. ResultsAdult-onset female mice consumed significantly more ethanol and displayed higher ethanol preference compared to adult-onset male mice. In contrast, adolescent-onset male and female mice consumed similar ethanol levels and displayed similar preference. We observed increased immobility during the forced swim test in adult-onset ethanol females, but not males, during protracted abstinence. However, both sexes of adolescent-onset ethanol mice displayed increased immobility during forced abstinence. ConclusionsThese findings highlight adolescence as a critical period during which both sexes voluntarily consume ethanol and are equally vulnerable to the behavioral disturbances associated with ethanol abstinence.

neuroscience↗

bioRxiv2024

A novel mouse home cage lickometer system reveals sex- and housing-based influences on alcohol drinking

Alcohol use disorder (AUD) is a significant global health issue. Despite historically higher rates among men, AUD prevalence and negative alcohol-related outcomes in women are rising. Loneliness in humans has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. We developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source tool to examine home cage continuous access two-bottle choice drinking behavior in a group-housed setting, investigating the influence of sex and social isolation on ethanol consumption and bout microstructure in C57Bl/6J mice. LIQ PARTI, based on our previously developed single-housed LIQ HD system, accurately tracks drinking behavior using capacitive-based sensors and RFID technology. Group-housed female mice exhibited higher ethanol preference than males, while males displayed a unique undulating pattern of ethanol preference linked to cage changes, suggesting a potential stress-related response. Chronic ethanol intake distinctly altered bout microstructure between male and female mice, highlighting sex and social environmental influences on drinking behavior. Social isolation with the LIQ HD system amplified fluid intake and ethanol preference in both sexes, accompanied by sex- and fluid-dependent changes in bout microstructure. However, these efects largely reversed upon resocialization, indicating the plasticity of these behaviors in response to social context. Utilizing a novel group-housed home cage lickometer device, our findings illustrate the critical interplay of sex and housing conditions in voluntary alcohol drinking behaviors in C57Bl/6J mice, facilitating nuanced insights into the potential contributions to AUD etiology. Significance StatementLoneliness has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. Here we developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source group-housed lickometer system to investigate how social housing, isolation, and sex influence alcohol consumption patterns in C57Bl/6J mice. LIQ PARTI accurately identifies mouse drinking events and uncovered significant housing- and fluid-dependent diferences in ethanol consumption and bout microstructure between male and female mice. Social isolation-induced changes to ethanol drinking behavior and microstructure were highly plastic, as resocialization generally reversed these changes. These findings expand on the complex interplay between sex, social isolation, and alcohol use.

neuroscience↗