Mechanisms of methamphetamine-induced dopaminergic neurotoxicity.
Methamphetamine (METH) is a powerful stimulant of abuse with potent addictive and neurotoxic properties. More than 2.5 decades ago, METH-induced damage to dopaminergic neurons was described. Since then, numerous advancements have been made in the search for the underlying mechanisms whereby METH causes these persistent dopaminergic deficits. Although our understanding of these mechanisms remains incomplete, combinations of various complex processes have been described around a central theme involving reactive species, such as reactive oxygen and/or nitrogen species (ROS and RNS, respectively). For example, METH-induced hyperthermia, aberrant dopamine(DA), or glutamate transmission; or mitochondrial disruption leads to the generation of reactive species with neurotoxic consequences. This review will describe the current understanding of how high-dose METH administration leads to the production of these toxic reactive species and consequent permanent dopaminergic deficits.
Riddle
Evan L
EL
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
Fleckenstein
Annette E
AE
Hanson
Glen R
GR
D000818:Animals; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects; D005334:Fever / Q000139:chemically induced; D006801:Humans; D008694:Methamphetamine / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D017382:Reactive Oxygen Species
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D008694:Methamphetamine; D004298:Dopamine