Adverse early-life conditions induce persistent disturbances that give rise to negative emotional states. Therefore, early life stress confers increased vulnerability to substance use disorders, mainly during adolescence as the brain is still developing. In this study, we investigated the consequences of maternal separation, a model of maternal neglect, on the psychotropic effects of cocaine and the neuroplasticity of the dopaminergic system. Our results show that mice exposed to maternal separation displayed attenuated behavioural sensitization, while no changes were found in the rewarding effects of cocaine in the conditioned place preference paradigm and in the reinforcing effects of cocaine in the self-administration paradigm. The evaluation of neuroplasticity in the striatal dopaminergic pathways revealed that mice exposed to maternal separation exhibited decreased protein expression levels of D2 receptors and increased levels of the transcriptional factor Nurr1. Furthermore, animals exposed to maternal separation and treated with cocaine exhibited increased DA turnover and protein expression levels of DAT and D2R, while decreased Nurr1 and Pitx3 protein expression levels were observed when compared with saline-treated mice. Taken together, our data demonstrate that maternal separation caused an impairment of cocaine-induced behavioural sensitization possibly due to a dysfunction of the dopaminergic system, a dysfunction that has been proposed as a factor of vulnerability for developing substance use disorders.

This study was supported by UE MedBioinformatics project (Grant Agreement Number: 634143), MINECO (SAF2013-41761-R-FEDER and SAF2013-49076-P-FEDER), Spanish Ministry of Health (Retic-ISCIII-RD/12/0028/0024-FEDER and RETICS-ISCIII-RD 12/0028/003-FEDER and Plan Nacional sobre Drogas 2014/020), Generalitat de Catalunya (2014SGR34) and Fundación Séneca (15405/PI/10), Región de Murcia. IG-R was funded by FPI fellowship BES-2011-046655 associated to SAF2010-15793.