title: Methamphetamine-induced rapid decrease in dopamine transporter function: role of dopamine and hyperthermia.
abstract: Single and multiple high-dose administrations of methamphetamine (METH) differentially decrease dopamine (DA) transporter (DAT) function, as assessed by measuring [(3)H]DA uptake into rat striatal synaptosomes prepared 1 h after treatment. Prevention of METH-induced hyperthermia attenuated the decrease in DAT activity induced by multiple injections of the stimulant. Likewise, this decrease was attenuated by previous depletion of striatal DA levels using alpha-methyl-p-tyrosine (alphaMT) or pretreatment with the D1 and D2 antagonists SCH-23390 and eticlopride, respectively. However, METH-induced hyperthermia was also blocked by alphaMT and eticlopride. Reinstatement of hyperthermia to alphaMT- or eticlopride-pretreated rats partially restored the METH-induced decrease in DAT activity. In contrast, neither prevention of METH-induced hyperthermia depletion of DA, nor DA antagonists altered the decrease in DAT function induced by a single administration of METH. Pretreatment with the antioxidant N-t-butyl-alpha-phenylnitrone prevented part of the decrease in DAT function associated with multiple, but not a single, METH injections. Although not tested directly, additional data presented here suggest that the reduction in DAT activity induced by a single METH administration constitutes a part of the total reduction observed immediately after multiple administrations. Taken together, the results indicate that DA, hyperthermia, and oxygen radicals contribute to a component of the rapid decrease in DAT function induced by multiple injections of METH but do not appear to be associated with the reduction induced by a single administration of the stimulant.
authors.affiliation: Program in Neuroscience, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Metzger
authors.forename: H M
authors.initials: HM
authors.lastname: Haughey
authors.forename: D G
authors.initials: DG
authors.lastname: Wilkins
authors.forename: J W
authors.initials: JW
authors.lastname: Gibb
authors.forename: G R
authors.initials: GR
authors.lastname: Hanson
authors.forename: A E
authors.initials: AE
authors.lastname: Fleckenstein
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins; D005334:Fever / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012701:Serotonin / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C493216:Slc6a3 protein, rat; D012701:Serotonin; D008694:Methamphetamine; D004298:Dopamine