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bioRxiv · 10.1101/2023.05.12.540565

Sex differences in binge alcohol drinking and the behavioral consequences of protracted withdrawal in C57BL/6J mice

Rivera-Irizarry, J. K.·Zallar, L. J.·Levine, O. B.·Skelly, M. J.·Boyce, J. E.·Barney, T.·Kopyto, R.·Pleil, K. E.
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Abstract

BackgroundBinge alcohol drinking is a risk factor linked to numerous disease states including alcohol use disorder (AUD). While men binge drink more alcohol than women, this demographic gap is quickly shrinking, and preclinical studies demonstrate that females consistently consume more alcohol than males. Further, women are at increased risk for the co-expression of AUD with neuropsychiatric diseases such as anxiety and mood disorders. However, little is understood about chronic voluntary alcohol drinking and its long-term effects on behavior. Here, we sought to characterize sex differences in chronic binge drinking and the effects of protracted alcohol abstinence on anxiety- and affective-related behaviors in males and females. MethodsWe assessed binge alcohol drinking patterns in male and female C57BL/6J mice using a modified Drinking in the Dark (DID) paradigm in which mice received home cage access to one bottle of 10% or 20% alcohol (EtOH) or water for 2 hrs per day on Days 1-3 and to two bottles (EtOH/H2O + H2O) for 24 hrs on Day 4 for eight weekly cycles. Mice were then tested for the effects of protracted abstinence on avoidance, affective, and compulsive behaviors. ResultsFemale mice consumed more alcohol than males consistently across cycles of DID and at 2, 4, and 24-hr timepoints within the day, with a more robust sex difference for 20% than 10% EtOH. Females also consumed more water than males, an effect that emerged at the later time points; this water consumption bias diminished when alcohol was available. Further, while increased alcohol consumption was correlated with decreased water consumption in males, there was no relationship between these two measures in females. Alcohol preference was higher in 10% vs. 20% EtOH for both sexes. During protracted abstinence following chronic binge drinking, mice displayed decreased avoidance behavior (elevated plus maze, open field, novelty suppressed feeding) and increased compulsive behavior (marble burying) that was especially robust in females. There was no effect of alcohol history on stress coping and negative affective behaviors (sucrose preference, forced swim test, tail suspension) in either sex. ConclusionFemale mice engaged in higher volume binge drinking than their male counterparts. Although females also consumed more water than males, their higher alcohol consumption was not driven by increased total fluid intake. Further, the effects of protracted abstinence following chronic binge drinking was driven by behavioral disinhibition that was more pronounced in females. Given the reciprocal relationship between risk-taking and alcohol use in neuropsychiatric disease states, these results have implications for sex-dependent alcohol drinking patterns and their long-term negative neuropsychiatric/physiological health outcomes in humans. SummaryThe overconsumption of alcohol is a widespread public health issue linked to numerous diseases and mental health issues including anxiety. Binge drinking, defined as having 4-5 drinks in a 2-hour period, is more common in men than women but that demographic gap is shrinking. Mice are commonly used as an animal model of alcohol consumption and binge drinking to study behaviors associated with/resulting from alcohol consumption. We found that female mice consumed more alcohol compared to their male counterparts. While female mice also drank more water than males, high alcohol consumption was not correlated with water consumption in females. In addition, following long-term alcohol consumption and protracted abstinence, mice displayed behavioral disinhibition marked by reduced avoidance and increased compulsive behavior; this phenotype was pronounced in females. As reduced adaptive anxiety/increased risk-taking behavior and alcohol consumption can promote one another, our results suggest that women may be especially vulnerable to the negative outcomes associated with chronic alcohol drinking. HighlightsO_LIFemale mice consistently consumed more alcohol per bodyweight than males, with a more robust sex difference for high (20%) than low (10%) concentration alcohol. C_LIO_LIFemales consumed more water than males at later (4-hr and 24-hr) but not early (2-hr) timepoints, and this effect was diminished when alcohol was available. C_LIO_LIHigher alcohol consumption was correlated with decreased water consumption in males but not females, suggesting that females greater alcohol consumption is not due to higher total fluid intake. C_LIO_LIAlcohol preference was higher for 10% versus 20% alcohol in both sexes. C_LIO_LIMice in protracted abstinence (2-6 wks) from binge alcohol drinking displayed a reduction in avoidance behavior and increase in compulsivity compared to water-drinking controls, especially in females. There was no effect of protracted alcohol abstinence on anhedonia in either sex. C_LI

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Rivera-Irizarry, J. K., Zallar, L. J., Levine, O. B., Skelly, M. J., Boyce, J. E., Barney, T., Kopyto, R., Pleil, K. E.. 2023-05-13. Sex differences in binge alcohol drinking and the behavioral consequences of protracted withdrawal in C57BL/6J mice. https://doi.org/10.1101/2023.05.12.540565

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