Sex-Specific patterns of vulnerability to alcohol addiction-like behaviors in rats.

Abstract

Only a minority of alcohol users develop alcohol use disorder (AUD), and the extent to which vulnerability to this condition depends on sex remains insufficiently explored in preclinical research. Using an established model that reverse-translates key diagnostic criteria for AUD, we investigated this question in male and female rats. Criteria for addiction-like behavior assessed were: (i) the inability to refrain from alcohol-seeking, (ii) high motivation for alcohol, and (iii) continued alcohol use despite negative consequences, assessed using footshock punishment. We found that a larger proportion of females (12.90%) met all three criteria compared to males (6.45%). Sex-differences observed were independent of alcohol consumption history, footshock sensitivity, or basal anxiety levels. Factor analysis results support the existence of both shared and sex-specific behavioral dimensions underlying addiction vulnerability. Notably, while persistence in alcohol-seeking and motivation loaded similarly onto "Factor 1" in both sexes, resistance to punishment showed opposite loadings on "Factor 3" in males and females. Moreover, this factor was differentially correlated with the global addiction score across sexes, indicating that this behavioral dimension may contribute differently to addiction-like behaviors in males and females. Notably, impulsivity was strongly correlated with the number of addiction-like criteria in both male and female rats, underscoring its broad role in shaping the risk. In contrast, neither anxiety-like behavior, locomotor activity in a novel environment, nor social dominance were predictors of addiction-like behaviors. These results emphasize the need for sex-specific approaches in AUD research, revealing complex behavioral traits that influence addiction risk.