While these data directly implicate sirtuins in regulating the rewarding effects of cocaine, cocaine addiction is marked by motivation to take drug, which is best assayed in the self-administration paradigm. Thus, we delivered sirtinol or vehicle via osmotic minipump directly into the NAc of rats, which were subsequently trained to self-administer cocaine. Sirtinol had no effect on the acquisition phase of cocaine self-administration (data not shown). However, while vehicle-infused rats displayed normal cocaine-seeking behavior throughout the ascending and descending limbs of the cocaine dose-response curve, sirtinol-infused rats displayed a dramatic reduction in cocaine self-administration (Fig. 5C). Sirtinol did not affect responding on the inactive nose poke aperture, which provides an important control for the lack of effect of sirtinol on general locomotor responses (Fig. 5D). These findings demonstrate that sirtuin activity in the NAc is an essential regulator of cocaine self-administration behavior, and further highlight the role played by this novel biochemical pathway in cocaine action.
