Early Life Stress Induces Anxiety‐like Hyperactivity but Not Altered Ethanol Drinking in Outbred Heterogeneous Stock Rats

Abstract

Early life stress (ELS) during adolescence is known to have lasting effects impacting vulnerability to psychopathological disorders in adulthood, including post‐traumatic stress disorder (PTSD) and alcohol use disorder (AUD). The mechanisms by which ELS affects an individual’s susceptibility to these psychopathological outcomes are not fully understood. There is evidence suggesting that genetics may play a role in susceptibility and resistance to ELS‐induced disorders, though few specific genes have been identified. Therefore, we investigated the outbred Heterogeneous Stock (HS) rat as a model to study the genetics contributing to ELS‐induced PTSD and AUD‐like behavior. The HS population has high genetic diversity and more closely resembles the range of phenotypes expected within a human population than inbred rodent strains. We hypothesized that adolescent social isolation (ASI) of HS rats would increase anxiety‐like behavior, induce hyperactivity in response to a novel environment, and increase ethanol self‐administration.In this study, we isolated (n=32) or group‐housed (n=32) male HS rats at 4 weeks of age. After 5 weeks of isolation (ISO) or group‐housing (GH), behavioral outcomes were measured via elevated plus maze (EPM), open field test (OFT), and forced swim test (FST). Following behavioral testing, all rats were individually housed and assessed for voluntary ethanol self‐administration.We found no differences between ISO and GH rats in EPM anxiety‐like behavior as measured via open arm time or closed arm time. However, we did find ISO increased hyperactivity in response to a novel environment compared to GH in the OFT, including increased movement time and distance, increased beam breaks, and increased rearing. Interestingly, we found that ISO rats demonstrated decreased despair‐like behavior in the FST, including decreased immobility and increased wall climbing. When presented with 20% ethanol, we found no difference in self‐administration between ISO and GH animals. At increasing concentrations of ethanol, GH rats appeared to consume more ethanol than ISO, though results did not reach significance. We observed high variability in individual propensity to self‐administer ethanol in both ISO and GH groups which may be playing a larger role than ELS in this population.We have shown that HS rats acquire hyperactivity in response to a novel environment following ELS but are resistant to ELS‐induced despair‐like behavior and alcohol consumption. There is literature to support ELS as a protective event in certain environmental situations. These results support the use of the HS rat as a model to investigate the genetics involved in resistance to ELS‐induced AUD.Support or Funding InformationFunding for this study was provided by the Wake Forest Center for Research on Substance Use and Addiction Pilot Grant with support from the Wake Forest Alcohol Center NIH/NIAAA award P50 AA26117.