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 SIRT1 or SIRT2. Consistent with the ChIP-chip, qChIP, and mRNA data, we found that chronic cocaine significantly increases both SIRT1 and SIRT2 catalytic activity in the NAc (Fig. 3C). Acute exposure to cocaine does not alter SIRT1 or SIRT2 activity, suggesting that the upregulation of sirtuins in NAc may contribute to the chronic neuroadaptations involved in drug addiction. Together, these data illustrate the predictive quality of our ChIP-chip analyses and suggest that our stringent cutoff of 3.1 SD may even underestimate the number of cocaine-regulated promoters.
