Figure 2:
Methamphetamine-induced changes in synaptic and intracellular pathways. Methamphetamine increases dopamine in the synaptic cleft and the cell via its effects on the cell surface dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT), respectively. Methamphetamine: (1) directly alters mitochondrial fusion and fission via sigma-1 receptor (σ1R binding leading to an increase in reactive oxygen species (ROS); (2) increases glutamatergic (GLU) transmission, which via increased intracellular calcium (Ca2+) and nitric oxide synthase (nNOS) leads to endoplasmic reticulum (ER) stress; and (3) binds to the toll-like 4 (TLR4) receptor to activate inflammatory pathways via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and tumor necrosis factor receptor associated factors (TRAF) to produce pro-inflammatory cytokines (IL6).