Methamphetamine toxicity and messengers of death

Abstract

Methamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, loss of gray matter accompanied by hypertrophy of the white matter and microgliosis in different brain areas. In the present review, we summarize data on the animal models of METH neurotoxicity which include degeneration of monoaminergic terminals and neuronal apoptosis. In addition, we discuss molecular and cellular bases of METH-induced neuropathologies. The accumulated evidence indicates that multiple events, including oxidative stress, excitotoxicity, hyperthermia, neuroinflammatory responses, mitochondrial dysfunction, and endoplasmic reticulum stress converge to mediate METH-induced terminal degeneration and neuronal apoptosis. When taken together, these findings suggest that pharmacological strategies geared towards the prevention and treatment of the deleterious effects of this drug will need to attack the various pathways that form the substrates of METH toxicity.

Figure 1

Schematic rendering of cellular and molecular events involved in METH-induced DA terminal degeneration and neuronal apoptosis within the striatum. The figure summarizes findings of various studies that have addressed the role of DA, oxidative stress, and other mechanisms in METH toxicity. METH enters dopaminergic neurons via DAT and passive diffusion. Within these neurons, METH enters synaptic vesicles through VMAT-2 and causes DA release into the cytoplasm via changes in pH balance. In the cytoplasm, DA auto-oxidizes to form toxic DA quinones with generation of superoxide radicals and hydrogen peroxides via quinone cycling. Subsequent formation of hydroxyl radicals through interactions of superoxides and hydrogen peroxide with transition metals leads to oxidative stress, mitochondrial dysfunctions and peroxidative damage to presynaptic membranes. The involvement of endogenous DA in METH neurotoxicity is supported by findings that the TH inhibitor, α-methyl-p-tyrosine, which blocks DA synthesis, affords protection against METH toxicity. In addition, the role of DA is supported by observations that use of the MAO inhibitor, clorgyline, and of the irreversible inhibitor of vesicular transport, reserpine, which results in increases in cytoplasmic DA levels can exacerbate METH-induced toxicity. Together, these events are thought to be partly responsible for the loss of DA terminals. DA release from the terminals is also involved because the DAT inhibitor, amphonelic acid, which blocks METH-induced DA release from DA terminals can also prevent damage to DA axons. The toxic effects of released DA might occur through activation of DA receptors because DA receptor antagonists block degeneration of DA terminals. Interactions of DA with D1 receptors on post-synaptic membrane cause activation of various transcription factors and subsequent upregulation of death cascades in postsynaptic neurons. These death cascades can be inhibited, in part, by the DA D1 antagonist, SCH23390.