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Vol. 295, Issue 3, 1077-1085, December 2000

Methamphetamine-Induced Rapid Decrease in Dopamine Transporter Function: Role of Dopamine and Hyperthermia1,2

Ryan R. Metzger, Heather M. Haughey, Diana G. Wilkins, James W. Gibb , Glen R. Hanson and Annette E. Fleckenstein

Department of Pharmacology and Toxicology (H.M.H., D.G.W., J.W.G., G.R.H., A.E.F.) and Program in Neuroscience (R.R.M., J.W.G., G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah

Single and multiple high-dose administrations of methamphetamine (METH) differentially decrease dopamine (DA) transporter (DAT) function, as assessed by measuring [3H]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 (alpha MT) or pretreatment with the D1 and D2 antagonists SCH-23390 and eticlopride, respectively. However, METH-induced hyperthermia was also blocked by alpha MT and eticlopride. Reinstatement of hyperthermia to alpha MT- 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.

1 This study was supported by U.S. Public Health Service Grants DA05859, DA11389, and DA00869.

2 This work was presented in part at the 29th Annual Meeting of the Society for Neuroscience; 1999 Oct 23-28; Miami Beach, FL.

0022-3565/00/2953-1077$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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