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bioRxiv · 10.1101/2025.03.06.641859

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

Edwards, C. M.·Xu, Z.·Winder, D.
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Abstract

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.

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Edwards, C. M., Xu, Z., Winder, D.. 2025-03-10. Adolescent onset of volitional ethanol intake normalizes sex differences observed with adult-onset ethanol intake and negative affective behaviors during protracted forced abstinence. https://doi.org/10.1101/2025.03.06.641859

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