Figure 10.

The nuclear effects of DRD1/PKA pathway and reactive species on postsynaptic neurons. The noncanonical DRD1 activation induced by METH produces an overactivation of several kinases, such as ERK1/2, DARPP-32-pT34, CREB, CDK5, and CaMKII. The latter, together with DA- and GLUT-derived reactive species, is shuttled into the nuclear compartment where they carry posttranslational modifications of histones and TFs. These events promote both a relaxation of chromatin structure (yielded by an increase of histone acetyltransferases (HAT)/decrease of histone deacetylases (HDAC)) and increased binding of TFs (such as Elk-1, AP-1, and CREB) at the level of their target gene sequences. These metabolic events eventually translate into an increase expression of IEGs.