Genetic inactivation of the CRF₂ receptor eliminates morphine-induced sociability deficits in female mice

Social behavior deficits, such as poor sociability and social isolation, are key clinical features of substance use disorders. The corticotropin-releasing factor (CRF) system may underlie the effects of substances of abuse but its implication in substance-induced social behavior deficits remains largely unknown. CRF signaling is mediated by two receptor types, termed CRF₁ and CRF₂. Using the genetic mouse model of CRF₂ receptor-deficiency and the three-chamber task for sociability, the present studies examined the specific role for the CRF₂ receptor in sociability deficits induced by morphine. Notably, to assess possible sex-linked differences, female and male CRF₂ receptor wild-type (CRF₂ WT) or knockout (CRF₂ KO) mice were used. Intraperitoneal administration of morphine (1 mg/kg) reliably eliminated the preference for an unfamiliar same-sex conspecific over an object in female CRF₂ WT, but not in CRF₂ KO, mice, revealing a key role for the CRF₂ receptor in opiate-induced sociability deficits. In contrast, morphine almost significantly and similarly reduced the preference for an unfamiliar same-sex conspecific over an object in male CRF₂ WT and CRF₂ KO mice, indicating no role for the CRF₂ receptor. Notably, treatment with morphine never affected distance travelled during the three-chamber test, indicating that CRF₂ receptor-dependent or -independent opiate effects were specific to social behavior. The present findings provide initial evidence of a critical sex-linked role for the CRF₂ receptor in social behavior deficits induced by opiate substances, suggesting new, sex-customized, therapeutic strategy for opioid use disorders.