We identified Sirt1 and Sirt2 from our ChIP-chip analyses of ΔFosB target genes that also were regulated by histone acetylation. We then identified significant increases in both Sirt1 and Sirt2 mRNA and protein activity in the NAc after chronic cocaine administration. We showed further that elevated sirtuin activity in the NAc increases the electrical excitability of NAc MSNs and potentiates the rewarding effects of cocaine. Finally, we demonstrated that pharmacological inhibition of sirtuins specifically in the NAc reduced both cocaine’s rewarding effects as well as the motivation to self-administer the drug. Thus, sirtuins appear to act downstream of ΔFosB and may contribute to a positive-feedback loop in which repeated drug exposure increases levels of ΔFosB and sirtuins, which in turn enhances the motivation to take additional drug. These findings raise the possibility of using SIRT1/2 inhibitors as potential treatment agents for cocaine addiction.
