Sexually dimorphic effects of a modified adolescent social isolation paradigm on behavioral risk factors of alcohol use disorder in Long Evans Rats

Early life stress (ELS) is a major risk factor for alcohol use disorder (AUD) and comorbid neuropsychiatric conditions. We previously demonstrated that an adolescent social isolation (aSI) model of ELS significantly increased behavioral risk factors for these disorders (e.g. anxiety-like behaviors, alcohol drinking) in male, but not female rats. Since many neurodevelopmental milestones are accelerated in females, we investigated whether an earlier/shorter isolation window (PND 21-38) would yield comparable phenotypes in both sexes. In two experiments, Long Evans rats were socially isolated (SI) or group-housed (GH) on postnatal day (PND) 21 and locomotion was assessed in the open field test (OFT; PND 30). Experiment 1 also assessed behavior on the elevated plus-maze (EPM) (PND 32). In Experiment 2, all rats were single housed on PND 38 to assess home cage alcohol drinking. Experiment 1 revealed that SI females had increased locomotor activity in the OFT but did not differ from GH subjects on the EPM. The OFT results were replicated in both sexes in Experiment 2 and both male and female SI rats had significantly greater ethanol consumption during an eight day continuous access paradigm. In contrast, during subsequent intermittent two-bottle choice drinking, only SI females displayed greater ethanol intake and preference and increased consumption of a quinine-adulterated alcohol solution. These findings demonstrate that early life social isolation can promote AUD vulnerability-related phenotypes in female rats but that there are profound sex differences in the vulnerability window to this early life stressor. Uncovering the neural mechanisms responsible for these sexually dimorphic differences in sensitivity to ELS may shed light on the biological substrates associated with vulnerability to AUD and comorbid disorders of negative emotion in men and women.