Our ChIP-chip studies identified significant enrichment of ΔFosB on the Sirt2 promoter after chronic cocaine exposure, indicating a potential role in cocaine responses (Fig. 3A, Table 1). After analyzing the promoter of Sirt2 in more detail, we noticed that there was also a strong increase in acetylated H3 downstream of the AP1/ΔFosB-binding site that we had overlooked because it fell just below the 3.1 SD cutoff. In an independent cohort of mice, we confirmed that chronic cocaine significantly increases levels of ΔFosB and acetylated H3 on the Sirt2 promoter (Fig. 3B) and that this is associated with increased Sirt2 mRNA expression in the NAc (Fig. 3B). Moreover, we found significant cocaine-induced H3 acetylation of a related sirtuin, Sirt1, in this brain region, a finding which we validated in an independent ChIP experiment and showed is associated with a significant increase in Sirt1 mRNA levels (Fig. 3A, 3B). To determine whether the increases observed in histone acetylation, ΔFosB-binding, and transcription of Sirt1 and Sirt2 are associated with changes in functional protein, we incubated cocaine-treated NAc lysates with a fluorescent substrate of
