Sex differences in ethanol consumption and drinking despite negative consequences following adolescent social isolation stress in male and female rats

Alcohol use disorder (AUD) is a debilitating psychiatric disorder characterized by drinking despite negative social and biological consequences. AUDs make up 71% of substance use disorders, with relapse rates as high as 80%. Current treatments stem from data conducted largely in males and fail to target the psychological distress motivating drinking in stress-vulnerable and at-risk populations. Here we employed a rat model and hypothesized that early life stress would reveal sex differences in ethanol intake and drinking despite negative consequences in adulthood. Rats were group housed or isolated postweaning to evaluate sex and stress effects on ethanol consumption in homecage drinking, self-administration (SA), and punished SA (drinking despite negative consequences) in adulthood. Stressed rats showed elevated homecage ethanol intake, an effect more pronounced in females. During SA, males were more sensitive to stress-induced elevations of drinking over time, but females drank more overall. Stressed rats, regardless of sex, responded more for ethanol than their non-stressed counterparts. Stressed females showed greater resistance to punishment-suppressed SA than stressed males, indicating a more stress-resistant drinking phenotype. Results support our hypothesis that adolescent social isolation stress enhances adult ethanol intake in a sex- and model-dependent manner with females being especially sensitive to early life stress-induced elevations in ethanol intake and punished SA in adulthood. Our findings echo the clinical literature which indicates that stress-vulnerable populations are more likely to 'selfmedicate' with substances. Elucidating a potential mechanism that underlies why vulnerable populations 'selfmedicate' with alcohol can lead towards developing catered pharmacotherapeutics that could reduce punishment-resistant drinking and relapse.