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Research ArticleNEUROPHARMACOLOGY

Methylenedioxymethamphetamine Decreases Plasmalemmal and Vesicular Dopamine Transport: Mechanisms and Implications for Neurotoxicity

J. Paul Hansen, Evan L. Riddle, Verónica Sandoval, Jeffrey M. Brown, James W. Gibb, Glen R. Hanson and Annette E. Fleckenstein
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 1093-1100; DOI: https://doi.org/10.1124/jpet.300.3.1093
J. Paul Hansen
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Evan L. Riddle
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Verónica Sandoval
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Jeffrey M. Brown
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James W. Gibb
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Glen R. Hanson
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Annette E. Fleckenstein
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Abstract

Administration of a high-dose regimen of methamphetamine (METH) rapidly and profoundly decreases plasmalemmal and vesicular dopamine (DA) transport in the striatum, as assessed in synaptosomes and purified vesicles, respectively. To determine whether these responses were common to other amphetamines of abuse, effects of methylenedioxymethamphetamine (MDMA) on the plasmalemmal DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) were assessed. Similar to effects of METH reported previously, multiple high-dose MDMA administrations rapidly (within 1 h) decreased plasmalemmal DA uptake, as assessed ex vivo in synaptosomes prepared from treated rats. Unlike effects of multiple METH injections, this deficit was reversed completely 24 h after drug treatment. Also in contrast to effects of multiple METH injections, 1) MDMA caused little or no decrease in binding of the DAT ligand WIN35428, and 2) neither prevention of hyperthermia nor prior depletion of DA prevented the MDMA-induced reduction in plasmalemmal DA transport. However, a role for phosphorylation was suggested because pretreatment with protein kinase C inhibitors attenuated the deficit caused by MDMA in an in vitro model system. In addition to affecting DAT function, MDMA rapidly decreased vesicular DA transport as assessed in striatal vesicles prepared from treated rats. Unlike effects of multiple METH injections reported previously, this decrease partially recovered by 24 h after drug treatment. Taken together, these results reveal several differences between effects of MDMA and previously reported METH on DAT and VMAT-2; differences that may underlie the dissimilar neurotoxic profile of these agents.

Footnotes

  • This study was supported by National Institute on Drug Abuse Grants DA11389, DA 00869, and DA 04222.

  • Abbreviations:
    MDMA
    methylenedioxymethamphetamine
    METH
    methamphetamine
    DA
    dopamine
    DAT
    dopamine transporter
    VMAT-2
    vesicular monoamine transporter-2
    PKC
    protein kinase C
    αMT
    α-methyl-p-tyrosine hydrochloride
    DHTBZ
    dihydrotetrabenazine
    • Received September 20, 2001.
    • Accepted December 5, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 3
1 Mar 2002
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Research ArticleNEUROPHARMACOLOGY

Methylenedioxymethamphetamine Decreases Plasmalemmal and Vesicular Dopamine Transport: Mechanisms and Implications for Neurotoxicity

J. Paul Hansen, Evan L. Riddle, Verónica Sandoval, Jeffrey M. Brown, James W. Gibb, Glen R. Hanson and Annette E. Fleckenstein
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1093-1100; DOI: https://doi.org/10.1124/jpet.300.3.1093

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Research ArticleNEUROPHARMACOLOGY

Methylenedioxymethamphetamine Decreases Plasmalemmal and Vesicular Dopamine Transport: Mechanisms and Implications for Neurotoxicity

J. Paul Hansen, Evan L. Riddle, Verónica Sandoval, Jeffrey M. Brown, James W. Gibb, Glen R. Hanson and Annette E. Fleckenstein
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1093-1100; DOI: https://doi.org/10.1124/jpet.300.3.1093
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