The CRF1 receptor mediates social behavior deficits induced by opiate withdrawal

Poor sociability and aggressive behavior are key clinical features of opioid use disorders. The corticotropin‐releasing factor (CRF) system may mediate behavioral effects of substances of abuse but its implication in substance‐induced social behavior deficits and outward‐directed hostility remains largely unknown. CRF signaling is mediated by two receptor types, termed CRF1 and CRF2. The present study aimed at understanding the role for the CRF1 receptor in social and aggressive behavior induced by withdrawal from repeated opiate administration. Thus, wild‐type (CRF1+/+), CRF1 receptor heterozygous (CRF1+/−), and null mutant (CRF1−/−) female and male mice were treated with saline or escalating doses of morphine (20‐100 mg/kg, i.p.) during six consecutive days and tested in the three‐chamber task for sociability (i.e., preference for an unfamiliar same‐sex conspecific vs. an object) 7 days after the last administration. Moreover, aggressive biting behavior toward the unfamiliar conspecific was assessed during the three‐chamber test. Opiate withdrawal disrupted sociability in CRF1+/+ and CRF1+/−, but not in CRF1−/−, female mice, without affecting aggressive biting behavior in any genotype. In contrast, opiate withdrawal did not affect sociability but increased aggressive biting behavior in male mice, independently of CRF1 receptor‐deficiency. Nevertheless, in opiate‐withdrawn CRF1+/+, but not CRF1+/− and CRF1−/−, male mice, sociability directly correlated with aggressive biting behavior, suggesting a role for the CRF1 receptor in hostility‐linked social approach. These findings demonstrate the implication of the CRF1 receptor in social behavior deficits associated with repeated opiate administration and withdrawal, revealing a new potential target for the treatment of opioid use disorders. Sociability deficits and aggressive behavior are common clinical features of opioid use disorders. Herein, genetic inactivation of the corticotropin‐releasing factor receptor 1 (CRF1) eliminated social approach deficits or hostility‐linked social approach in morphine‐withdrawn female or male mice, respectively. Thus, reduction of CRF1 receptor activity might ameliorate sociability of opiate‐dependent patients.