Corticotropin-releasing hormone signaling from piriform cortex to amygdala mediates social homophily in opioid addiction.

Social partner selection can significantly influence one's social well-being, emotional support, and even cognitive functions. Drug-abstinent mice exhibit sociability deficits, yet how drug-addicted individuals select their social partners and how these choices influence addiction-related behaviors remain unclear. In this study, we demonstrate that opioid-experienced mice prefer socializing with opioid-experienced peers. Presentation of an opioid-abstinent demonstrator mouse or its olfactory cues (not ultrasound or visual cues) enhances corticotropin-releasing hormone (CRH) release from the anterior piriform cortex (APIR) to the basomedial amygdala (BMA) in abstinent observer mice. This CRH release occurs specifically during approach, acts through CRH receptor 1/2 in the BMA, and enhances social motivation. Disruption of this social homophily impairs addiction-related memory and relapse in opioid-abstinent mice. Our findings reveal social homophily in opioid-experienced individuals, elucidate the underlying APIR-BMA CRH signaling mechanism, and underscore the importance of social support from non-addicted peers for opioid-abstinent individuals during recovery.