The cocaine-induced upregulation of SIRT1 and SIRT2 in the NAc prompted us to examine how these enzymes affect the physiological activity of NAc neurons. To do this, we performed whole-cell current-clamp recordings of medium spiny neurons (MSNs) in acute NAc slices incubated with a pharmacological inhibitor (sirtinol) or activator (resveratrol) of sirtuins. We found that 30 μM sirtinol nearly silenced NAc neurons, reducing the number of spikes elicited by 100 pA current injection by ~90% compared to vehicle (0.1% DMSO). Moreover, the minimum amount of current needed to elicit an action potential (rheobase) was significantly higher in sirtinol-treated slices (Fig. 4A), consistent with a decrease in NAc MSN excitability (Fig. 4B). Conversely, the sirtuin activator resveratrol (50 μM) potently increased NAc MSN excitability while reducing rheobase, suggesting that cocaine-induced increases in SIRT1 and SIRT2 activity may be associated with increased NAc excitability. Individual traces are shown in Fig. 4C, which illustrate the dramatic effects of inhibiting or activating sirtuins on the functional activity of NAc MSN neurons.
