Methamphetamine-induced rapid decrease in dopamine transporter function: role of dopamine and hyperthermia.
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.
Metzger
R R
RR
Program in Neuroscience, University of Utah, Salt Lake City, Utah 84112, USA.
Haughey
H M
HM
Wilkins
D G
DG
Gibb
J W
JW
Hanson
G R
GR
Fleckenstein
A E
AE
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
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