Figure 1.

Drugs of abuse increase the levels of brain oxidative stress and trigger a self-perpetuating cycle that sustains neuroinflammation. Drugs of abuse promote the release of dopamine (DA), which is either rapidly spontaneously oxidized or metabolized via monoamine oxidase B (MAO-B) and cyclooxygenase 1/2 (COX1/2), generating superoxide ion and hydrogen peroxide, thus increasing oxidative stress. Oxidative stress generated by drugs of abuse can impair mitochondrial function, further increasing oxidative stress production. The rise in oxidative stress promotes the nuclear translocation and activation of NF-κB in microglia. Cocaine, ethanol, and opioids promote the activation of Toll-like receptor 4 (TLR4), which also activates microglial NF-κB. In the nucleus, NF-κB promotes the increase in the expression of the pro-oxidant enzymes NADPH-oxidase (NOX) and inducible nitric oxide synthase (iNOS), and of pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1). The increase of oxidative stress and pro-inflammatory cytokines promote the activation of microglia and astrocytes via the activation of NF-κB directly or via additional mitochondrial impairment, which further perpetuates the brain oxidative stress and inflammation cycle.