In addition to identifying novel pathways involved in cocaine action, we have gained new insight into the layers of complex regulation that control these pathways. For most of the pathways we investigated, chronic cocaine promotes the expression of an intricate network of activating and inhibiting molecules. This is surprising because we know that many of these same pathways are functionally upregulated several fold after chronic cocaine. For example, in the NFκB pathway, there is increased acetylation on the genes coding both the transcriptional activator, p50, and its inhibitor, IκB (see Fig. 6B). However, we know that NFκB activity is upregulated in the NAc after chronic cocaine (Ang et al., 2001; Russo et al., 2009), suggesting that the increased acetylation on IκB may serve to limit the primary activation of p50 and its upstream activators, TNFR and TRAF1. Similar complex regulation is seen for the dopamine-cAMP pathway. Cocaine functionally upregulates cAMP signaling in NAc (Carlezon et al., 2005), but simultaneously increases histone acetylation on the genes for the Gi-coupled D3 receptor and an inhibitor of Gi-signaling, RGS9. The NFκB and cAMP
