title: An acute, epitope-specific modification in the dopamine transporter associated with methamphetamine-induced neurotoxicity.
abstract: Preclinical studies demonstrate that repeated, high-dose methamphetamine administrations rapidly decrease plasmalemmal dopamine uptake, which may contribute to aberrant dopamine accumulation, reactive species generation, and long-term dopaminergic deficits. The present study extends these findings by demonstrating a heretofore unreported, epitope-specific modification in the dopamine transporter caused by a methamphetamine regimen that induces these deficits. Specifically, repeated, high-dose methamphetamine injections (4 × 10 mg/kg/injection, 2-h intervals) rapidly decreased immunohistochemical detection of striatal dopamine transporter as assessed 1 h after the final methamphetamine exposure. In contrast, neither a single high dose (1 × 10 mg/kg) nor repeated injections of a lower dose (4 × 2 mg/kg/injection) induced this change. The high-dose regimen-induced alteration was only detected using antibodies directed against the N-terminus. Immunohistochemical staining using antibodies directed against the C-terminus did not reveal any changes. The high-dose regimen also did not alter dopamine transporter expression as assessed using [(125) I]RTI-55 autoradiography. These data suggest that the repeated, high-dose methamphetamine regimen alters the N-terminus of the dopamine transporter. Further, these data may be predictive of persistent dopamine deficits caused by the stimulant. Future studies of the signaling cascades involved should provide novel insight into potential mechanisms underlying the physiological and pathophysiological regulation of the dopamine transporter.
authors.affiliation: Department of Psychology and Neuroscience, Regis University, Denver, Colorado, 80221.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Fricks-Gleason
authors.affiliation: School of Dentistry, University of Utah, Salt Lake City, Utah, 84108.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: German
authors.affiliation: School of Dentistry, University of Utah, Salt Lake City, Utah, 84108.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Hoonakker
authors.affiliation: Eating and Addiction Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, 20892.|Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Friend
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Kamala K
authors.initials: KK
authors.lastname: Ganesh
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Carver
authors.affiliation: School of Dentistry, University of Utah, Salt Lake City, Utah, 84108.|Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Hanson
authors.affiliation: School of Dentistry, University of Utah, Salt Lake City, Utah, 84108.|Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Annette E
authors.initials: AE
authors.lastname: Fleckenstein
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah, 84112.|Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, 84112.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Keefe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D000939:Epitopes / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008969:Molecular Sequence Data; D011485:Protein Binding; D000072417:Protein Domains; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D000939:Epitopes; D008694:Methamphetamine
keywords: N-terminus; immunohistochemistry; rodent; striatum; toxicity