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Early‐life stress (ELS) is associated with negative consequences, including maladaptive long‐lasting brain effects. These alterations seem to increase the likelihood of developing substance use disorders. However, the molecular consequences of ELS are poorly understood. In the present study, we tested the impact of ELS induced by maternal separation with early weaning (MSEW) in CD1 male mice at different phases of cocaine self‐administration (SA). We also investigated the subsequent alterations on GluR2, GluR1, cAMP response element‐binding (CREB), and CREB‐phosphorylation (pCREB) in ventral tegmental area (VTA) and nucleus accumbens (NAc) induced by both MSEW and cocaine SA. Our results show that MSEW animals expressed a higher cocaine intake, an increased vulnerability to the acquisition of cocaine SA, and incapacity to extinguish cocaine SA behaviour. MSEW mice showed decreased GluR2 and increased GluR1 and pCREB in NAc. Also, results displayed reduction of basal levels of GluR1 and CREB and an elevation of GluR1/GluR2 ratio in the VTA. Such results hint at an enhanced glutamatergic function in NAc and increased excitability of VTA DA neurons in maternally separated mice. Altogether, our results suggest that MSEW induces molecular alterations in the brain areas related to reward processing, increasing the vulnerability to depression and cocaine‐seeking behaviour.

Social defeat stress induces a long-lasting increase in anxiety like behavior. • Social defeat stress enhances rewarding properties of cocaine. • Social defeat stress increase BDNF levels in prefrontal cortex. • Oxytocin treatment favors the extinction of cocaine-associated memories. • Oxytocin administration counteracts stress effect in anxiety and in BDNF levels.