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The neuropeptide oxytocin (OXT) plays a critical role in the regulation of social and emotional behaviors. OXT plays a role in stress response and in drug reward, but to date no studies have evaluated its implication in the long-lasting increase of the motivational effects of cocaine induced by repeated social defeat (RSD). During the social defeat procedure, 1 mg/kg of OXT was administered 30 min before each episode of RSD. Three weeks after the last defeat, the effects of cocaine on the conditioned place preference (CPP), locomotor sensitization and the self-administration (SA) paradigms were evaluated. The influence of OXT on the levels of BDNF in the prefrontal cortex (PFC), striatum and hippocampus was also measured. Our results confirm that raising the levels of OXT during social defeat stress can block the long-lasting effects of this type of stress. OXT counteracts the anxiety induced by social defeat and modifies BDNF levels in all the structures we have studied. Moreover, OXT prevents RSD-induced increases in the motivational effects of cocaine. Administration of OXT before each social defeat blocked the social defeat-induced increment in the conditioned rewarding effects of cocaine in the CPP, favored the extinction of cocaine-associated memories in both the CPP and SA, and decreased reinstatement of cocaine-seeking behavior in the SA. In conclusion, the long-lasting effects of RSD are counteracted by administering OXT prior to stress, and changes in BDNF expression may underlie these protective effects. ; This work was supported by the Ministerio de Economía y Competitividad, Dirección General de Investigación, [grant numbers PSI2014-51847-R and PSI 2017-83023-R]; Spanish Ministry of Economy, Innovation and Competiveness (SAF2016-75347-R). Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) [grant numbers RETICS RD06/0001/1006; RD12/0028/0005; and RD/16/0017/0010] and Unión Europea, Fondos FEDER "A way to build Europe". The Department of Experimental and Health Sciences (UPF) is an "Unidad de Excelencia María de Maeztu" funded by the MINECO (Ref. MDM2014-0370). A.C-Z received CONACYT grant from the Government of Mexico. M.A.L. and C.F.P received FPU grant from the Spanish Ministry of Economy, Innovation and Competiveness (15/02492 and 14/02279).