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. Author manuscript; available in PMC: 2014 Jul 18.
Published in final edited form as: Adv Pharmacol. 2014;69:1–69. doi: 10.1016/B978-0-12-420118-7.00001-9

Figure 1.

Figure 1

Psychostimulants increase synaptic damage through direct actions on neurons and glia including both microglia and astroglia. Psychostimulants damage presynaptic terminals of neurons causing the production of reactive oxygen (ROS) and nitrogen (species), and the production of damage-associated molecular patterns (DAMPs) that trigger activation of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and other PRRs associated with microglia, and to a lesser extent astroglia. Dopaminergic neurons are particularly vulnerable to methamphetamine, which disrupts dopamine transporter (DAT) and vesicular monoamine transporter 1 (VMAT2) function. Importantly, psychostimulants disrupt glial function directly by increasing intracellular Ca2+ concentration ([Ca2+]i), NF-κB transcriptional activity, and by activating sigma1-receptors (sigma1-R) and enzyme systems driving oxidative and nitrosative stress especially in microglia (and other cell types). Increases in NF-κB transcriptional activity result in the increased production of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6) (among others) cytokines by microglia and to a lesser degree by astroglia. Psychostimulants also obstruct the buffering of extracellular glutamate by inhibiting excitatory amino acid transporters-1/2 (EAAT1/2) and the conversion of glutamate to glutamine by inhibiting glutamine synthetase, as well as limiting glucose metabolism in astrocytes. Collectively, neuronal damage combined with a heightened state of glial activation promotes positive microglial-astroglial, and neuronal-glial feedback that cause spiraling increases in neuroinflammation and neuronal injury. If unchecked, the cumulative insults result in lasting neurodegenerative changes. Modified and reprinted from reference (Hauser et al., 2012)—an “open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.”