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 Nevertheless, in opiate-withdrawn CRF₁ +/+, but not CRF₁ +/- and CRF₁ -/-, male mice, sociability directly correlated with aggressive biting behavior, suggesting a role for the CRF₁ receptor in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.