# Sex-Based Mechanisms of Stress-Induced Alcohol-Seeking

## TL;DR

This study explores how sex differences influence stress-induced alcohol-seeking and identifies potential mechanisms involving brain connectivity and subjective responses to alcohol.

## Contribution

The study identifies sex-specific neural and subjective mechanisms linking anxiety and stress-induced alcohol-seeking.

## Key findings

- Generalized anxiety symptoms were significantly associated with greater stress-induced alcohol-seeking in women but not in men.
- Blunted state stimulation in response to alcohol was associated with greater stress-induced alcohol-seeking across both sexes.
- Resting-state network connectivity revealed potential sex-dependent neural mechanisms related to alcohol-seeking.

## Abstract

Sex differences in stress-induced alcohol-seeking are well documented. The overarching goal of this study is to examine how sex may moderate the relationship between depression and anxiety symptoms and stress-induced alcohol-seeking and to identify mechanisms of this relationship. We explore subjective alcohol responses and the resting-state functional connectivity of the amygdala and the hippocampus, regions implicated in anxiety and depression, as potential sex-dependent mediators. This secondary analysis draws from a recently published trial of 84 adults aged 21 to 55 (54.8% female, mean age = 32, SD = 10.68; 58.3% White, 88.1% non-Hispanic/Latino) who endorsed moderate-to-heavy alcohol use. All participants completed two counterbalanced intravenous alcohol administration sessions, and 54 completed optional neuroimaging. Generalized anxiety symptoms were significantly associated with greater stress-induced alcohol-seeking in women but not in men. Depression symptoms showed a similar pattern, though the results did not reach statistical significance. Across men and women, blunted state stimulation, but not state anxiety, in response to alcohol was associated with greater stress-induced alcohol-seeking. In men, anxiety symptoms were linked with heightened state stimulation effects, which appeared to buffer against stress-induced alcohol-seeking. State stimulation findings may suggest a possible mechanism for sex differences concerning anxiety pathways to alcohol-seeking. Subjective alcohol responses did not mediate the relationship between depression symptoms and stress-induced alcohol-seeking. Resting-state network connectivity findings identified several potential sex-dependent neural mechanisms that warrant further investigation. Although this study was not originally designed as a direct test of competing subjective response and low-level response to alcohol theoretical models, our findings are consistent with Schuckit’s low level of response to alcohol theory. Our findings showed that blunted stimulation may contribute to stress-induced alcohol-seeking among men. Identifying mechanisms that underlie sex-specific relationships with stress-induced alcohol-seeking can inform the development of tailored intervention approaches, ultimately enhancing treatment efficacy for both men and women.