Inhibition of Class I and II HDAC’s in the NAc has been shown to increase behavioral sensitivity to cocaine (Kumar et al., 2005; Renthal et al., 2007), while we show here that inhibition of Class III HDAC’s (sirtuins) reduces it. Given the role of sirtuins in regulating numerous cytosolic substrates apart from histone proteins, it is possible that these downstream effectors are more important contributors than histone deacetylation to sirtuin regulation of cocaine action. Indeed, it was recently shown in primary neuronal cultures that SIRT1 is required for normal activation of ERK, a protein well known to exert potent control over behavioral responses to cocaine (Li et al., 2008). To determine if ERK activation requires SIRT activity in the adult NAc, we used ex vivo slice pharmacology to bathe NAc slices in a depolarizing buffer (to induce ERK activation) plus either sirtinol or vehicle. We observed a significant reduction in ERK1/2 phosphorylation in the sirtinol-treated NAc while total ERK1/2 levels remained unchanged (Fig. 5E). These findings demonstrate that sirtinol inhibits ERK activation in the NAc, which may be one mechanism by which sirtinol antagonizes NAc excitability as well as cocaine reward and self-administration.
