The induction of immediate early genes such as c-fos by cocaine or amphetamine after repeated drug exposure is strongly attenuated, a point at which histone H4 on c-fos promoter is hypoacetylated [53, 59]. In addition to desensitizing immediate early genes, repeated cocaine exposure (either forced- or self-administered) is also known to induce a distinct set of genes in the NAc (e.g. cdk5 and bdnf), some of which remain elevated for days to weeks [13, 16, 60, 61]. Consistent with such stable changes in gene expression, increased histone H3 acetylation was observed on the gene promoters of both cdk5 and bdnf for 1–7 days following the final dose of cocaine [53]. Stable changes in histone acetylation and gene expression have been observed for nearly two weeks following withdrawal from cocaine self-administration in the prefrontal cortex as well [52]. For example, npy (neuropeptide Y) expression was found to be upregulated and its gene promoter hyperacetylated, while egr-1 (early growth response 1) was found to be downregulated and hypoacetylated after cocaine withdrawal [52]. Together, these findings tightly correlate gene activity in the brain
