Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression, that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor ?FosB and protein kinase CaMKII are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that ?FosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, where it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation (ChIP) assays, we found that ?FosB binds the CaMKIIα gene promoter in NAc, and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of ?FosB to the CaMKIIα promoter, and reduces CaMKII expression in NAc, despite the fact that ?FosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIα promoter which blocks ?FosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine 9 dimethylation of histone H3 at the CaMKIIα promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, while inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIα expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.Neuropsychopharmacology accepted article preview online, 15 November 2013. doi:10.1038/npp.2013.319.