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Although chronic cocaine-induced changes in dendritic spines on nucleus accumbens (NAc) neurons have been correlated with behavioral sensitization, the molecular pathways governing these structural changes, and their resulting behavioral effects, are poorly understood. The transcription factor, nuclear factor κ B (NFκB), is rapidly activated by diverse stimuli and regulates expression of many genes known to maintain cell structure. Therefore, we evaluated the role of NFκB in regulating cocaine-induced dendritic spine changes on medium spiny neurons of the NAc and the rewarding effects of cocaine. We show that chronic cocaine induces NFκB-dependent transcription in the NAc of NFκB-Lac transgenic mice. This induction of NFκB activity is accompanied by increased expression of several NFκB genes, the promoters of which show chromatin modifications after chronic cocaine exposure consistent with their …