The oxytocin system mediates behavioral and neurobiological alterations associated with early adversity.

Early life adversities (ELA) can significantly impact brain development and adult behavior, potentially increasing vulnerability to psychopathologies. Evidence shows that ELA exposure is significantly associated with dysfunctional Oxytocin (OXT), a neuropeptide strongly engaged in social behavior and linked to the processing of rewarding stimuli, such as drugs of abuse. Moreover, it has been recently demonstrated that peripheral OXT may be transported to the brain through several mechanisms, including Receptors for Advanced Glycation End-Products (RAGE), and the RAGE-mediated OXT transport has been shown to play a key critical role in mediating some aspects of social behavior, such as social bonding. However, how OXT system alterations induced by ELA could increase vulnerability to psychopathologies is still under investigation. To investigate this link, we exploit our model of early adversity (Repeated Cross-Fostering, RCF), known to increase the sensitivity to cocaine effects in adult C57BL/6 J (C57) female mice acting on the dopaminergic mesocorticolimbic system. Here, we show that in C57 females, RCF manipulation also impairs social recognition and impacts the OXT system by altering i) OXT levels in the brain and plasma; ii) the expression of RAGE; and iii) the expression of OXT receptor (OxtR). Notably, early restoring brain and plasmatic OXT levels via subcutaneous OXT injection during RCF manipulation counteracts the RCF-induced neurobiological alterations of the OXT system and prevents short and long-lasting behavioral alterations. These findings shed light on the mechanisms by which the oxytocinergic system mediates the long-term effects of early-life adversities on drug addiction vulnerability and social behavior.