To gain a more global view of the genes regulated by cocaine in the NAc, we subjected our gene sets to Ingenuity molecular pathway analysis software (see Supplemental Fig. S3). The most significantly regulated molecular pathways based on altered histone acetylation were cAMP signaling, long term potentiation or depression, RXR signaling, and neurotrophin signaling (e.g., ERK/MAP kinase and PTEN/PI-3-kinase/Akt) pathways. Each of these pathways is known to play integral roles in the cellular and behavioral responses to chronic cocaine, and their enrichment in our analyses supports the predictive quality of this study. Notably, chronic cocaine also regulated several glutamate receptors and downstream calcium signaling molecules, including subunits of NMDA and AMPA receptors, metabotropic receptors, and HOMER3. The upregulation of glutamate signaling is consistent with previous reports, which demonstrate that chronic cocaine increases the sensitivity of NAc neurons to glutamate (Kalivas, 2004). Examples of these highly regulated pathways are shown in Figs. 6A and 6B. The panels illustrate the profound and complex effects of cocaine on second messenger- and growth factor-regulated molecular pathways in the NAc, and how the individual genes
