Much interest has been piqued regarding the quality of one's environment at early ages in modulating the susceptibility to drug addiction in adulthood. However, the molecular mechanisms that are engaged during early trauma and mediate the risk for drug addiction are poorly understood. In rodents, exposure to early-life stress alters the rewarding effects of cocaine, amphetamine, and morphine in adulthood. Recently, we demonstrated that the exposure of juvenile mice to social threat (Social Stress, S-S) promoted cocaine-seeking behavior and relapse of cocaine-seeking after periods of withdrawal, compared with unhandled controls (UN) and with juvenile mice that experienced only daily isolation in a novel environment (no social stress, NS-S). Interestingly, while the exposure to NS-S slightly increased cocaine-seeking behavior compared with UN, the same was not sufficient to promote cocaine reinstatement. In this study, we examined the long-term transcriptional changes that are induced by S-S compared to NS-S and linked the increased susceptibility of S-S mice to cocaine reinstatement. To this end, we performed genome-wide RNA sequencing analysis in the nucleus accumbens (NAC), which revealed that 89 transcripts were differentially expressed between S-S and NS-S mice. By Gene Ontology classification, these hits were enriched in genes that mediate cell proliferation, neuronal differentiation, and neuron/forebrain development. Eleven of these genes have been reported to be involved in substance use disorders, and the remaining genes are novel candidates in this area. We characterized 4 candidates with regard to their significant neurobiological relevance (ZIC1, ZIC2, FABP7, and PRDM12) and measured their expression in the NAC by immunohistochemistry. These findings provide insights into novel molecular mechanisms in NAC that might be associated with the risk of relapse in cocaine-dependent individuals.