that this action influences gene expression in response to cocaine and thereby controls behavioral responses to the drug. Indeed, chromatin immunoprecipitation (ChIP) assays from mouse striatal tissues have revealed that chronic cocaine treatment induced marked increases in acetylation state of core histones in the promoter regions of the FosB, brain-derived neurotropic factor (BDNF), and Cdk5 genes,44 which have all been implicated in regulating the motivational properties of cocaine. Histone acetylation is catalyzed by histone acetyltransferases (HATs) and deacetylation is catalyzed by histone deacetylases (HDACs). HDACs catalyze the removal of acetyl groups from histone tails, resulting in more tightly compacted DNA-histone complexes, decreased access of transcription factors to gene promoter regions, and reductions in gene expression. Importantly, chronic but not acute cocaine treatment decreased the function of histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAcc) of mice,57 an action of cocaine that may explain the observed increase in acetylation of core histones in the promoter regions of FosB, BDNF, and Cdk5 genes and the wellcharacterized increase in the expression of their associated proteins after chronic cocaine exposure.58-62 Further, viral-mediated overexpression of HDACs in striatal tissues decreased,44,57 whereas genetic or pharmacological knockout of striatal HDACs increased sensitivity to the rewarding effects
