title: The newly synthesized pool of dopamine determines the severity of methamphetamine-induced neurotoxicity.
abstract: The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH-induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH-induced neurotoxicity. l-DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO-A by clorgyline increases pre-synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre-synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, l-DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH-induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug-induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH.
authors: Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA. dthomas@med.wayne.edu
authors: David M
authors: DM
authors: Thomas
authors: Dina M
authors: DM
authors: Francescutti-Verbeem
authors: Donald M
authors: DM
authors: Kuhn
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis*; D015259:Dopamine Agents / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007980:Levodopa / Q000494:pharmacology; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D008694:Methamphetamine; D007980:Levodopa; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D004298:Dopamine