Early life stress modulates behavioral sensitivity to alcohol and promotes escalation of alcohol drinking

Morningstar, A. R.; Ledbury, O. S.; Yu, A. C.; Sardar, H.; Rogers, E. T.; Kandil, I. F.; Fajardo, R. N.; Benabou, M. E.; Giardino, W. J.

doi:10.1101/2025.06.27.661986

bioRxiv · 10.1101/2025.06.27.661986

Early life stress modulates behavioral sensitivity to alcohol and promotes escalation of alcohol drinking

Morningstar, A. R.·Ledbury, O. S.·Yu, A. C.·Sardar, H.·Rogers, E. T.·Kandil, I. F.·Fajardo, R. N.·Benabou, M. E.·Giardino, W. J.

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Abstract

Adverse childhood experiences significantly increase the risk of developing alcohol use disorder (AUD) in adulthood. We used a model of combined limited bedding/nesting and maternal separation (LBN+MS) in C57BL/6J background mice to investigate how early life stress (ELS) modulates behavioral sensitivity to alcohol, long-term alcohol drinking patterns, and the effects of alcohol on social behaviors. Our findings reveal that ELS increased sensitivity to the stimulatory locomotor effects of alcohol (1.75 g/kg) selectively in females and reduced sensitivity to the sedative effects of alcohol (4.0 g/kg) particularly in males. This pattern of enhanced stimulation and diminished sedation is consistent with phenotypes observed in human subjects at high risk for developing AUD. ELS also significantly enhanced escalation of voluntary alcohol intake and preference over eight weeks of two-bottle choice intermittent access drinking particularly in males. Additionally, social behavior assessments revealed that ELS impaired sociability selectively in females with a history of alcohol drinking, highlighting the detrimental interactive effects of ELS and alcohol exposure on adaptive behaviors. These results underscore the complex interplay between ELS, alcohol responses, and sex differences, suggesting that ELS creates a high-risk phenotype for AUD through altered alcohol behavioral sensitivity. Our study highlights the importance of future studies that seek to identify the neurobiological mechanisms underlying these interactions, which may pave the way for targeted interventions in populations affected by childhood adversity and excessive alcohol consumption.

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Morningstar, A. R., Ledbury, O. S., Yu, A. C., Sardar, H., Rogers, E. T., Kandil, I. F., Fajardo, R. N., Benabou, M. E., Giardino, W. J.. 2025-06-28. Early life stress modulates behavioral sensitivity to alcohol and promotes escalation of alcohol drinking. https://doi.org/10.1101/2025.06.27.661986

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