Nitric oxide (NO) and the C-type natriuretic peptide (CNP) exert their action via stimulation of the cyclic GMP (cGMP)-signaling pathway, which includes the activation of cGMP-dependent protein kinases (PKG). The present report shows that the activation of PKG by local application of 8-bromo-cGMP in the caudate–putamen reduced the expression of the epigenetic markers, methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2), in dopaminergic projection areas of cocaine-treated rats. An effect of lesser amplitude was observed when rats were not injected with cocaine. We also studied the effect of PKG overexpression by injecting a plasmid vector containing the human PKG-Iα cDNA in either the caudate–putamen or the ventral tegmental area. Injection in the caudate–putamen reduced the epigenetic parameters with higher amplitude than the cGMP analog. The effect was abolished by the injection of a selective PKG inhibitor, confirming that it was due to PKG-dependent phosphorylation. As MeCP2 and HDAC2 modulate dynamic functions in the adult brain such as memory formation and synaptic plasticity, the downregulation of expression by PKG suggests that the cGMP pathway affects cognitive processes through a mechanism that comprises the MeCP2/HDAC2 complex and the subsequent control of gene silencing.