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Research ArticleNEUROPHARMACOLOGY

Amphetamine Inhibits theN-Methyl-d-Aspartate Receptor-Mediated Responses by Directly Interacting with The Receptor/Channel Complex

Geng-Chang Yeh, Jin-Chung Chen, Hsiu-Chuan Tsai, Hsueh-Hsia Wu, Chao-Yu Lin, Ping-Ching Hsu and Yu-Chen Peng
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 1008-1016; DOI: https://doi.org/10.1124/jpet.300.3.1008
Geng-Chang Yeh
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Jin-Chung Chen
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Hsiu-Chuan Tsai
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Hsueh-Hsia Wu
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Chao-Yu Lin
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Ping-Ching Hsu
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Yu-Chen Peng
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Abstract

Amphetamine (AMPH) induces behavioral sensitization and neurotoxicity primarily by enhancing the dopamine-mediated neurotransmission. However, the involvement of theN-methyl-d-aspartate (NMDA) receptor in AMPH-induced neuropathology is also known. Recent investigation has found that high concentration of dopamine could inhibit NMDA receptor-mediated responses by blocking the NMDA receptor channel. By virtue of the structure similarity between dopamine and AMPH, we determined whether d-AMPH and its analogs,l-AMPH and methamphetamine (MAMH), could affect the NMDA receptor-mediated [3H]N-[1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP) binding in rat cortical membrane preparations and intracellular 45Ca2+accumulation and cell death in the rat primary cortical cell cultures. AMPH concentration-dependently inhibited NMDA- and glycine-stimulated [3H]TCP binding and intracellular45Ca2+ accumulation with two distinct potencies; a minor inhibition with high potency and a major inhibition with low potency. [3H]TCP binding suggested that the high-potency inhibition was produced by decreasing agonist-induced activation of the NMDA receptor channel. On the other hand, the low-potency inhibition was produced by competing with [3H]TCP binding in the NMDA receptor channel, like the action of noncompetitive antagonist of the NMDA receptor. However, AMPH analogs were less potent in inhibiting NMDA- and glycine-induced cultured cell death. Thus, this result indicates that AMPH could antagonize the NMDA receptor-mediated responses in vitro by two different mechanisms, probably, through directly interacting with two distinct sites on this receptor/channel complex.

Footnotes

  • ↵1 Present address: Department of Pharmacology, Chang-Gung University.

  • ↵2 Present address: Department of Medical Technology, Taipei Medical University.

  • This work is supported by National Science Council of Taiwan Grants 85–2331-B-038–027-M27 and 86–2314-B-038–006.

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    AMPH
    amphetamine
    MAMH
    methamphetamine
    [3H]TCP
    [3H]N-[1-(2-thienyl)cyclohexyl] piperidine
    LDH
    lactose dehydrogenase
    MEM
    modified Eagle's medium
    d-APV
    2-amino-5-phosphopentanoic acid
    7-CKA
    7-cholorkyneurenic acid
    PCP
    phencyclidine
    ANOVA
    analysis of variance
    MAMPH
    d-methamphetamine
    • Received August 21, 2001.
    • Accepted November 21, 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

Amphetamine Inhibits theN-Methyl-d-Aspartate Receptor-Mediated Responses by Directly Interacting with The Receptor/Channel Complex

Geng-Chang Yeh, Jin-Chung Chen, Hsiu-Chuan Tsai, Hsueh-Hsia Wu, Chao-Yu Lin, Ping-Ching Hsu and Yu-Chen Peng
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1008-1016; DOI: https://doi.org/10.1124/jpet.300.3.1008

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Research ArticleNEUROPHARMACOLOGY

Amphetamine Inhibits theN-Methyl-d-Aspartate Receptor-Mediated Responses by Directly Interacting with The Receptor/Channel Complex

Geng-Chang Yeh, Jin-Chung Chen, Hsiu-Chuan Tsai, Hsueh-Hsia Wu, Chao-Yu Lin, Ping-Ching Hsu and Yu-Chen Peng
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1008-1016; DOI: https://doi.org/10.1124/jpet.300.3.1008
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