Our data demonstrate that the HDAC Sir2 promotes changes in locomotor behavior elicited by repeated ethanol exposure, and also promotes sensitivity to the sedative actions of ethanol. Recent findings have shown that the sirtuins, through their actions as HDACs, influence animal behavior, including circadian rhythms and the rewarding properties of cocaine (Nakahata et al., 2009; Renthal et al., 2009). It is likely that histone acetylation also regulates the physiological effects of ethanol exposure: HDAC activity is decreased in the amygdala following acute ethanol exposure in rats, and hepatocyte cell culture studies identified increased histone acetylation following ethanol exposure (Pandey et al., 2008; Park et al., 2003). Additionally, repeated exposure of Drosophila to benzyl alcohol, which may affect flies in a manner similar to ethanol, revealed tolerance to recovery from sedation that is accompanied by increased histone acetylation, and these effects were mimicked by an HDAC inhibitor (Wang et al., 2007). Sir2 is likely expressed in all tissues, and ethanol-dependent changes in protein acetylation levels may be equally widespread.
