# Adolescent Binge Ethanol Exposure Confers Lasting Adult Alcohol Tolerance due to Neuroimmune Activation: Reversal by Inhibition of HMGB1

## TL;DR

Adolescent binge drinking leads to lasting alcohol tolerance in adulthood, which can be reversed by inhibiting HMGB1, a protein involved in inflammation.

## Contribution

This study identifies HMGB1 signaling as a reversible driver of alcohol tolerance caused by adolescent binge drinking.

## Key findings

- Adolescent binge ethanol exposure leads to long-lasting alcohol tolerance in adulthood.
- HMGB1 inhibition reverses alcohol tolerance induced by adolescent binge drinking.
- Neuroimmune activation, particularly involving HMGB1, contributes to the development of alcohol tolerance.

## Abstract

Epidemiological studies suggest heavy adolescent binge drinking is strongly associated with later development of an alcohol use disorder (AUD). Alcohol tolerance (i.e., an acquired reduction in acute alcohol responsivity) is a universally recognized symptom of AUD, but the direct contribution of adolescent binge drinking to adult alcohol tolerance is poorly understood. To investigate the contributions of adolescent binge ethanol exposure to lasting acquisition of acute tolerance, we used our ethanol response battery (ERB) to assess intoxication rating, hypothermia, motor coordination and balance across cumulative ethanol doses (i.e., 0.0, 0.5, 1.0, 2.0 and 3.0 g/kg) in adult female Wistar rats following adolescent intermittent ethanol (AIE), lipopolysaccharide (LPS) and glycyrrhizic acid treatment following AIE. We report AIE confers lasting alcohol tolerance across cumulative ethanol doses and blunts acute ethanol‐induced increases in proinflammatory HMGB1 plasma levels. Adolescent LPS (1.0 mg/kg, i.p.) treatment, which mimics AIE‐induced HMGB1‐mediated neuroinflammation, induces adult alcohol tolerance and blunts HMGB1 release across cumulative ethanol doses on the ERB. Assessment of proinflammatory HMGB1 involvement in AIE‐induced acquisition of lasting alcohol tolerance showed that post‐AIE administration of the HMGB1 inhibitor glycyrrhizic acid reversed the AIE‐induced acquisition of alcohol tolerance in adulthood. These data reveal that (1) adolescent binge drinking confers long‐lasting low ethanol responsivity (i.e., tolerance), (2) proinflammatory neuroimmune activation contributes to the development of alcohol tolerance and (3) blockade of proinflammatory HMGB1 signalling reverses AIE‐induced acquisition of alcohol tolerance in adulthood. These findings suggest a potential mechanistic target for the development of novel therapeutics for the treatment of AUD.

Adolescent intermittent ethanol (AIE) exposure induces enduring adult alcohol tolerance across a cumulative ethanol response battery. Parallel adolescent lipopolysaccharide challenge recapitulated tolerance and blunted acute ethanol–evoked HMGB1 release, implicating neuroimmune programming. Post‐AIE administration of the HMGB1 inhibitor glycyrrhizic acid normalized behavioural and physiological responsivity, and reduced HMGB1/RAGE/NF‐κB indices, identifying HMGB1 signalling as a reversible mechanistic driver of tolerance and a therapeutic target for AUD.