title: Role of dopamine transporter in methamphetamine-induced neurotoxicity: evidence from mice lacking the transporter.
abstract: The role of the dopamine transporter (DAT) in mediating the neurotoxic effects of methamphetamine (METH) was tested in mice lacking DAT. Dopamine (DA) and serotonin (5-HT) content, glial fibrillary acidic protein (GFAP) expression, and free radical formation were assessed as markers of METH neurotoxicity in the striatum and/or hippocampus of wild-type, heterozygote, and homozygote (DAT -/-) mice. Four injections of METH (15 mg/kg, s.c.), each given 2 hr apart, produced 80 and 30% decreases in striatal DA and 5-HT levels, respectively, in wild-type animals 2 d after administration. In addition, GFAP mRNA and protein expression levels, extracellular DA levels, and free radical formation were increased markedly. Hippocampal 5-HT content was decreased significantly as well (43%). Conversely, no significant changes were observed in total DA content, GFAP expression, extracellular DA levels, or free radical formation in the striatum of DAT -/- mice after METH administration. However, modest decreases were observed in striatal and hippocampal 5-HT levels (10 and 17%, respectively). These observations demonstrate that DAT is required for, and DA is an essential mediator of, METH-induced striatal dopaminergic neurotoxicity, whereas serotonergic deficits are only partially dependent on DAT.
authors.affiliation: Howard Hughes Medical Institute Laboratories, Department of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: F
authors.initials: F
authors.lastname: Fumagalli
authors.forename: R R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: K J
authors.initials: KJ
authors.lastname: Valenzano
authors.forename: M G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000818:Animals; D015415:Biomarkers; D001831:Body Temperature / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D015870:Gene Expression / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology*; D017551:Microdialysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin / Q000032:analysis / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D017382:Reactive Oxygen Species; C493215:Slc6a3 protein, mouse; D012701:Serotonin; D008694:Methamphetamine; D004298:Dopamine