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
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This work was supported by United States Public Health Service Awards DA-09487, DA-05707, DA-05938, and DA-10217.
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The Department of Neurology at Johns Hopkins University School of Medicine is the laboratory of origin for this research.
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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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