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Research ArticleNEUROPHARMACOLOGY

Toward Development of an In Vitro Model of Methamphetamine-Induced Dopamine Nerve Terminal Toxicity

Saejeong Kim, Robert Westphalen, Brian Callahan, George Hatzidimitriou, Jie Yuan and George A. Ricaurte
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 625-633;
Saejeong Kim
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Robert Westphalen
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Brian Callahan
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George Hatzidimitriou
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Jie Yuan
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George A. Ricaurte
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Abstract

To develop an in vitro model of methamphetamine (METH)-induced dopamine (DA) neurotoxicity, striatal synaptosomes were incubated at 37°C with METH for different periods of time (10–80 min), washed once, then tested for DA transporter function at 37°C. METH produced time- and dose-dependent reductions in the Vmax of DA uptake, without producing any change in Km. Incubation of synaptosomes with the DA neurotoxins 1-methyl-4-phenyl-pyridinium ion, 6-hydroxydopamine, and amphetamine under similar conditions produced comparable effects. In contrast, incubation with fenfluramine, a serotonin neurotoxin, did not. METH-induced decreases in DA uptake were selective, insofar as striatal glutamate uptake was unaffected. Various DA transporter blockers (cocaine, methylphenidate, and bupropion) afforded complete protection against METH-induced decreases in DA uptake, without producing any effect themselves. METH's effects were also temperature dependent, with greater decreases in DA uptake occurring at higher temperatures. Tests for residual drug revealed small amounts (0.1–0.2 μM) of remaining METH, but kinetic studies indicated that decreases in DA uptake were not likely to be due to METH acting as a competitive inhibitor of DA uptake. Decreases in theVmax of DA uptake were not accompanied by decreases in Bmax of [3H]WIN 35,428 binding, possibly because there is no mechanism for removing damaged DA nerve endings from the in vitro preparation Collectively, these results give good support to the development of a valid in vitro model that may prove helpful for elucidating the mechanisms underlying METH-induced DA neurotoxicity.

Footnotes

  • Send reprint requests to: George A. Ricaurte, M.D., Ph.D., Department of Neurology, Johns Hopkins Medical Institutions, 5501 Hopkins Bayview Circle, Room 5B71E, Baltimore, MD 21224. E-mail:ricaurte{at}jhmi.edu

  • ↵1 This study was supported by National Institutes of Health Grants PHS R01 DA06275, DA05707, DA05938, DA10217, and K02 DA00206 (to G.A.R.).

  • Abbreviations:
    METH
    methamphetamine
    DA
    dopamine
    6-OHDA
    6-hydroxydopamine
    AMPH
    amphetamine
    ROS
    reactive oxygen species
    MPP+
    1-methyl-4-phenyl-pyridinium
    BIS
    bisindolylmaleimide I
    RIA
    radioimmunoassay
    DAT
    DA transporter
    PKC
    protein kinase C
    • Received October 19, 1999.
    • Accepted January 20, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleNEUROPHARMACOLOGY

Toward Development of an In Vitro Model of Methamphetamine-Induced Dopamine Nerve Terminal Toxicity

Saejeong Kim, Robert Westphalen, Brian Callahan, George Hatzidimitriou, Jie Yuan and George A. Ricaurte
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 625-633;

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Research ArticleNEUROPHARMACOLOGY

Toward Development of an In Vitro Model of Methamphetamine-Induced Dopamine Nerve Terminal Toxicity

Saejeong Kim, Robert Westphalen, Brian Callahan, George Hatzidimitriou, Jie Yuan and George A. Ricaurte
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 625-633;
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