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Research ArticleNEUROPHARMACOLOGY

Effect of Glucoprivation on Serotonin Neurotoxicity Induced by Substituted Amphetamines

Jie Yuan, Branden J. Cord, Una D. McCann, Brian T. Callahan and George A. Ricaurte
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 831-839; DOI: https://doi.org/10.1124/jpet.102.041277
Jie Yuan
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Branden J. Cord
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Una D. McCann
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Brian T. Callahan
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George A. Ricaurte
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Abstract

The present studies were conducted to further explore the potential role of metabolic compromise in substituted amphetamine-induced serotonin (5-HT) neurotoxicity. To this end, we examined the glucoprivic effects of 2-deoxy-d-glucose (2-DG) on the 5-HT neurotoxic effects of fenfluramine (FEN) and methylenedioxymethamphetamine (MDMA). Rats were treated with either FEN or MDMA, alone and in combination, with doses of 2-DG known to produce glucoprivic effects at either 22 ± 1 or 28 ± 1°C. At 22 ± 1°C, FEN produced hypothermia, MDMA induced hyperthermia, and both drugs produced significant long-term reductions in regional brain 5-HT neuronal markers. 2-DG did not enhance 5-HT neurotoxicity induced by either FEN or MDMA; indeed, in some instances, it afforded partial neuroprotection. Although 2-DG afforded partial protection from both FEN and MDMA-induced 5-HT neurotoxic changes, it also caused significant hypothermia, raising the possibility that protection was due to a lowered temperature. Increasing the ambient temperature to 28 ± 1°C largely eliminated drug-induced hypothermia and eliminated the neuroprotective effects of 2-DG. Thus, even without the confounding effect of temperature, 2-DG still did not potentiate FEN or MDMA-induced 5-HT neurotoxicity. These findings suggest that the role of metabolic compromise in amphetamine-induced 5-HT neurotoxicity merits further study.

Footnotes

  • This work was supported by United States Public Health Service Awards DA-09487, DA-05707, DA-05938, and DA-10217.

  • The Department of Neurology at Johns Hopkins University School of Medicine is the laboratory of origin for this research.

  • DOI: 10.1124/jpet.102.041277

  • Abbreviations:
    FEN
    fenfluramine
    MDMA
    3,4- methylenedioxymethamphetamine
    5-HT
    serotonin
    METH
    methamphetamine
    DA
    dopamine
    2-DG
    2-deoxy-d-glucose
    5-HIAA
    5-hydroxyindoleacetic acid
    5-HTT
    5-HT transporter
    ANOVA
    analysis of variance
    AUC
    area under the curve
    • Received July 9, 2002.
    • Accepted July 25, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleNEUROPHARMACOLOGY

Effect of Glucoprivation on Serotonin Neurotoxicity Induced by Substituted Amphetamines

Jie Yuan, Branden J. Cord, Una D. McCann, Brian T. Callahan and George A. Ricaurte
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 831-839; DOI: https://doi.org/10.1124/jpet.102.041277

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Research ArticleNEUROPHARMACOLOGY

Effect of Glucoprivation on Serotonin Neurotoxicity Induced by Substituted Amphetamines

Jie Yuan, Branden J. Cord, Una D. McCann, Brian T. Callahan and George A. Ricaurte
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 831-839; DOI: https://doi.org/10.1124/jpet.102.041277
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