Repeated cocaine administration induced hyperacetylation of histone H3 at 959 gene promoters in NAc and hypoacetylation at 83 gene promoters compared to saline-treated controls (Fig. 1A). Similarly, chronic cocaine caused hyperacetylation of histone H4 at 692 gene promoters and hyopacetylation at 123. It is interesting to note that several fold more genes showed H3 or H4 hyperacetylation after chronic cocaine compared to hypoacetylation. This is consistent with our earlier findings, from DNA expression arrays, that the predominant effect of cocaine is gene activation (McClung and Nestler, 2003; Renthal et al., 2007), and with more recent findings that reductions in histone acetylation block cocaine’s behavioral effects while increases in acetylation augment cocaine action (Kumar et al., 2005; Renthal et al., 2007). A striking finding from the present study is that only about 15% of regulated gene promoters showed increased acetylation of both H3 and H4 (see Fig. 1A). Even less overlap was observed with genes hypoacetylated at H3 and H4 (1%). While these overlaps are statistically significant, the very small amount of overlap suggests that acetylation of one histone is sufficient
