Epigenetic Effects Induced by Methamphetamine and Methamphetamine-Dependent Oxidative Stress

Figure 8

METH-induced noncanonical DRD1 signaling. Following METH, MSNs become supersensitive to pulsatile DA stimulation despite that the number of DA receptors is not increased. As a result, DRD1 move towards noncanonical signaling and the activity of DRD2 is enhanced. In these conditions, DRD1 overactivates AC, which enhances the production of cAMP and leads to abnormal activation of PKA. DRD1/PKA cascade turns out to increase the amount of DARPP-32 phosphorylated at Thr34, which inhibits PP1. Thus, all PKA targets, including voltage-gated ion channels and GLUT NMDAr and AMPAr, are abnormally phosphorylated and activated. In addition, DRD1/PKA leads to increased levels of MAPK and ERK1/2, which in turn phosphorylate several cytosolic and nuclear substrates. At the same time, DRD2-enhanced activity potentiates the increase of intracellular Ca2+ release, which cannot be properly mobilized, since ion channels and GLUT receptors are abnormally activated and potentiate the influx of Ca2+ within postsynaptic neurons. Such an event also promotes the activation of calmodulin-dependent kinase II (CaMKII), which can translocate into the nucleus to regulate gene expression.