Stressfulexperience-induced cocaine-related behaviors were associated with a significantimpairment of glutamatergic mechanisms in the nucleus accumbens core (NAcc).NF-kB, a ubiquitous transcription factor, induce the expression of gene targetstightly linked to glia maintenance of glutamate homeostasis. Here, using agenetic and pharmacological strategy, we evaluate the impact of NF-kBabrogation in NAcc on the long-term expression of restraint stress-inducedbehavioral cross-sensitization to cocaine. Thus, we used lentiviral vectorsexpressing a dominant negative to the IKK (dn IKK) and the potentpharmacological inhibitor of NF-kB nuclear translocation, PDTC, to nullify thetranscription factor activity. Chronically pre-stressed were administeredintra-NAcc with dnIKK 7 days, or PDTC 20 minutes before a cocaine challengeadministration, respectively. After treatment, behavioral sensitization andNF-kB levels were evaluated. Repeated stress induced a significant NF-kBactivation in the NAcc. Consistently, the pharmacological or genetic inhibitionof NF-kB activation, was sufficient to prevent stress-induced sensitization tococaine. These results suggest a central role of NF-kB on the long-term neurobiologicalmechanism induced by stress in the NAcc, promoting the expression ofcross-sensitization to cocaine. Furthermore, our findings help to understandthe neural and molecular basis of the comorbidity between exposure to stressand cocaine abuse.