Abstract
Use of the popular club drug ecstasy (3,4-methylenedioxymethamphetamine, MDMA) can result in life-threatening hyperthermia and rhabdomyolysis. Recent studies show a link between skeletal muscle uncoupling proteins in MDMA-mediated hyperthermia. The mechanisms by which MDMA interacts with skeletal muscle mitochondria are largely unknown. The present study was designed to comprehensively evaluate the effects of MDMA on bioenergetics and toxicity of skeletal muscle. Using 31P nuclear magnetic resonance (NMR) and serum creatine kinase levels, we demonstrate evidence for uncoupling of oxidative phosphorylation in the skeletal muscle of MDMA (40 mg/kg)-treated rats. In vivo, rats treated with MDMA had significantly elevated serum creatine kinase levels, a marker of rhabdomyolysis, 4 h post-MDMA treatment (955 ± 132 IU/l) compared with saline-treated controls (373.2 ± 59 IU/l). β-ATP signal areas after MDMA treatment showed significant reductions (15%) from the baseline values with corresponding increases in inorganic phosphate (88% increases) and decreases in intracellular pH. Clark electrode experiments on isolated skeletal muscle mitochondria in vitro (1–5 mM MDMA) and ex vivo in MDMA-treated animals demonstrated no evidence of uncoupling of oxidative phosphorylation. In vitro experiments using L6 myotubules cocultured with primary hepatocytes demonstrated the presence of uncoupling protein-3 in the L6 myotubules, but no evidence of a direct effect of MDMA or its potential metabolites on cellular creatine kinase concentrations. These findings suggest that MDMA uncouples skeletal muscle mitochondria in vivo but that this uncoupling is the result of indirect mechanisms.
Footnotes
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This study was supported by a Clarian Value Funds grant, Clarian Health Systems, Indianapolis, Indiana.
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Part of this work was presented at the 2004 Society for Academic Emergency Medicine Meeting, Orlando, Florida, May 2004.
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doi:10.1124/jpet.104.079236.
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ABBREVIATIONS: MDMA, 3,4-methylenedioxymethamphetamine; AR, adrenergic receptor; UCP, uncoupling protein; JVC, jugular vein cannulated; PPA, phenylphosphonic acid; MOPS, 4-morpholinepropanesulfonic acid; RCI, respiratory control index; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; DPBS, Dulbecco's phosphate-buffered saline; ADP/O, ADP to oxygen ratio.
- Received October 13, 2004.
- Accepted January 10, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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