As stated earlier, repeated cocaine administration induces CREB activity in the NAc, which then feeds back and attenuates the rewarding effects of cocaine (Carlezon et al., 2005). Cocaine activates CREB by increasing its phosphorylation at Ser133. Phosphorylation of CREB, which is often bound to responsive genes at CRE (cAMP response element) sites even in the absence of its phosphorylation, contributes to the recruitment of transcriptional co-activators such as the histone acetyltransferase, CBP (CREB binding protein), to promote gene transcription (Mayr and Montminy, 2001). Therefore, to gain insight into the transcriptional actions of CREB in the NAc after chronic cocaine, we carried out ChIP for phospho-CREB followed by promoter array assays. These data were then analyzed as described above for ΔFosB, by generating a high-confidence list of gene targets with a false discovery rate of 5%. After chronic cocaine exposure, we found that phospho-CREB was bound significantly to the promoters of 1743 genes, approximately 38% more genes than were occupied in saline-treated mice (1259) (Fig. 2A; Supplemental Tables S9 and S10). Roughly 12% of the phospho-CREB-bound genes after chronic cocaine exhibited
