Figure 6.

The effects of extracellular DA released following METH. Extracellular DA and DA-derived reactive species diffuse at considerable distance towards nonneuronal targets including the neurovascular unit (blood-brain barrier (BBB) and Glia), which is affected by METH (1). At short distance, METH produces an abnormal stimulation of postsynaptic neurons, mainly striatal MSNs. The pulsatile pattern of DA stimulation produces an abnormal pulsatile activation of postsynaptic DA D1 receptors (DRD1) (2). This leads to a series of noncanonical metabolic changes, which translate into activation of glutamate (GLUT) receptors N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (NMDAr and AMPAr, resp.) (3) potentiation of GLUT release and Ca2+ entry within postsynaptic neurons (4). This event triggers an enzymatic cascade further increasing reactive oxygen species (ROS) and nitrogen species (RNS) (5). Freely diffusible DA-derived free radicals together with GLUT-derived radical species synergize to produce detrimental effects on postsynaptic non-DA neurons. These consist in DNA instability, due to oxidative damage (fragmentation and/strand breaks) and alterations in gene expression (A), mitochondrial stress (B), and oxidation of organic substrates, mainly proteins, which are prone to misfold and produce insoluble aggregates leading to an impairment of cell-clearing systems (C).