Sex‐linked roles of the CRF <sub>1</sub> and the CRF <sub>2</sub> receptor in social behavior
Alessandro Piccin, Angelo Contarino
Abstract
Abstract Dysfunctional social behavior is a major clinical feature of mood, anxiety, autism spectrum, and substance‐related disorders, and may dramatically contribute to the poor outcome of these diseases. Nevertheless, the mechanisms underlying social behavior deficits are still largely unknown. The corticotropin‐releasing factor (CRF) system, a major coordinator of the stress response, has been hypothesized to modulate social behavior. CRF signaling is mediated by two receptor types, termed CRF 1 and CRF 2 . Using the three‐chamber task for sociability (i.e., preference for an unfamiliar conspecific vs. an object), this study demonstrates that CRF 2 receptor null mutation (CRF 2 −/−) reduces sociability in female mice but increases it in male mice. Both female and male CRF 2 −/− mice display a preference for social odor cues over neutral cues, indicating that sex‐ and CRF 2 receptor‐dependent sociability is not due to altered olfaction or impaired social cues discrimination. Moreover, treatment with the CRF 1 receptor‐preferring antagonist, antalarmin, consistently induces sociability in non‐social mice but disrupts it in social mice, independently of CRF 2 receptor deficiency. Sex, CRF 2 receptor deficiency, or antalarmin affect locomotor activity during the three‐chamber test. However, throughout the study CRF 1 and CRF 2 receptor‐linked sociability is independent of locomotor activity. The present findings highlight major functions for the CRF system in the regulation of social behavior. Moreover, they provide initial evidence of sex‐linked roles for the CRF 1 and the CRF 2 receptor, emphasizing the importance of sex as a major biological variable to be taken into consideration in preclinical and clinical studies.