PT - JOURNAL ARTICLE AU - Laura A. Grafe AU - Darrell Eacret AU - Jane Dobkin AU - Seema Bhatnagar TI - Reduced Orexin System Function Contributes to Resilience to Repeated Social Stress AID - 10.1523/ENEURO.0273-17.2018 DP - 2018 Mar 01 TA - eneuro PG - ENEURO.0273-17.2018 VI - 5 IP - 2 4099 - http://www.eneuro.org/content/5/2/ENEURO.0273-17.2018.short 4100 - http://www.eneuro.org/content/5/2/ENEURO.0273-17.2018.full SO - eNeuro2018 Mar 01; 5 AB - Exposure to stress increases the risk of developing affective disorders such as depression and post-traumatic stress disorder (PTSD). However, these disorders occur in only a subset of individuals, those that are more vulnerable to the effects of stress, whereas others remain resilient. The coping style adopted to deal with the stressor, either passive or active coping, is related to vulnerability or resilience, respectively. Important neural substrates that mediate responses to a stressor are the orexins. These neuropeptides are altered in the cerebrospinal fluid of patients with stress-related illnesses such as depression and PTSD. The present experiments used a rodent social defeat model that generates actively coping rats and passively coping rats, which we have previously shown exhibit resilient and vulnerable profiles, respectively, to examine if orexins play a role in these stress-induced phenotypes. In situ radiolabeling and qPCR revealed that actively coping rats expressed significantly lower prepro-orexin mRNA compared with passively coping rats. This led to the hypothesis that lower levels of orexins contribute to resilience to repeated social stress. To test this hypothesis, rats first underwent 5 d of social defeat to establish active and passive coping phenotypes. Then, orexin neurons were inhibited before each social defeat for three additional days using designer receptors exclusively activated by designer drugs (DREADDs). Inhibition of orexins increased social interaction behavior and decreased depressive-like behavior in the vulnerable population of rats. Indeed, these data suggest that lowering orexins promoted resilience to social defeat and may be an important target for treatment of stress-related disorders.