title: Dopamine disposition in the presynaptic process regulates the severity of methamphetamine-induced neurotoxicity.
abstract: Methamphetamine (METH) is well known for its ability to cause damage to dopamine (DA) nerve endings of the striatum. The mechanisms by which METH causes neurotoxicity are not fully understood, but likely candidates are increased oxidative and nitrosative stress and mitochondrial dysfunction. Microglial activation is also emerging as an important element of the METH neurotoxic cascade, and it appears that extensive cross-talk between these cells and DA nerve endings is an early event in this process. It may seem paradoxical, but DA itself is also thought to be an essential factor in the neuronal damaging effects of METH, but issues relating to its precise role in this regard remain unanswered. We present in this overview a summary of studies that tested how alterations in the disposition of presynaptic DA (injections of reserpine, L-DOPA, or clorgyline) modulate METH neurotoxicity. In all cases, these drugs significantly increased the magnitude of microglial activation as well as the severity of damage to striatal DA nerve endings caused by METH. The enhancement of METH effects in striatum by reserpine, L-DOPA, and clorgyline persisted for 14 days and showed no evidence of recovery. These data establish that subtle shifts in the newly synthesized pool of DA can cause substantial changes in the severity of METH-induced neurotoxicity. DA released into the synapse by METH is very likely the source of downstream reactants that provoke microglial activation and the ensuing damage to DA nerve endings.
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA. donald.kuhn@wayne.edu
authors.forename: Donald M
authors.initials: DM
authors.lastname: Kuhn
authors.forename: Dina M
authors.initials: DM
authors.lastname: Francescutti-Verbeem
authors.forename: David M
authors.initials: DM
authors.lastname: Thomas
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000633:toxicity; D003010:Clorgyline / Q000494:pharmacology; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D008694:Methamphetamine / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D008996:Monoamine Oxidase Inhibitors; D009498:Neurotoxins; D008694:Methamphetamine; D007980:Levodopa; D012110:Reserpine; D003010:Clorgyline; D004298:Dopamine