The Role of Mitochondrial Uncoupling in 3,4-Methylenedioxymethamphetamine-Mediated Skeletal Muscle Hyperthermia and Rhabdomyolysis

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 31 P 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 Ϯ 132 IU/l) compared with saline-treated controls (373.2 Ϯ 59 IU/l). ␤-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.

The Agony of Ecstasy

“…The hyperpyrexia is likely due to activation of 5-hydroxytryptamine and dopamine receptor systems, which are effectors of thermoregulation and activate mechanisms that both conserve and generate heat (30,31). Another mechanism may be related to the effects of MDMA to uncouple skeletal muscle mitochondria in vivo, generating increased thermogenesis (26,32). These effects on thermogenesis are greatly compounded by the ambient temperature, which in crowded rave parties is usually elevated.…”

“…This case represents the most common scenario that is associated with the development of AKI: Nontraumatic rhabdomyolysis (1,2). Rhabdomyolysis is likely secondary to ecstasy-induced seizures or repetitive muscular activity or perhaps due to a direct toxic effect of the drug on skeletal myocytes (26). In the majority of these cases, patients have been exerting themselves to excessive levels with inadequate hydration compounded by impaired thermoregulation and hyperpyrexia (6,(27)(28)(29).…”

3,4-Methylenedioxymethamphetamine (Ecstasy) Activates Skeletal Muscle Nicotinic Acetylcholine Receptors

“…Caffeine was purchased from Merck (Darmstadt, Germany), MDMA and ryanodine were from Sigma Chemie (Deisenhofen, Germany), and pure, i.e., preservativefree, 2% SCh was from Curamed Pharma (Karlsruhe, Germany). Corresponding to MDMA concentrations applied in other nonperfused tissue preparations (Leonardi and Azmitia, 1994;Carvalho et al, 2002;Rusyniak et al, 2005), we used 100 to 1000 (4000) M.…”

“…These adverse effects point to the skeletal muscle or the neuromuscular junction as a target of MDMA outside the central nervous system. Metabolic myopathies have been postulated to be the cause of these severe crises , and recently, MDMA has been proposed to uncouple oxidative phosphorylation in skeletal muscle mitochondria by an indirect mechanism (Rusyniak et al, 2005). Toxic rhabdomyolyses have been reported in healthy individuals for a variety of substances, including statins, amphetamines, opiates, and succinylcholine (SCh).…”

Microinjection of muscimol into the dorsomedial hypothalamus suppresses MDMA-evoked sympathetic and behavioral responses

“…In anesthetized animals, a condition in which animals are incapable of experiencing exteroceptive or "emotional" stress, administration of MDMA still evokes increases in heart rate, mean arterial pressure and body temperature (Blessing et al, 2003; Rusyniak et al, 2005a;Rusyniak et al, 2005b). Likewise, in humans recreational doses of MDMA (doses chosen by users presumably for pleasureprovoking responses) cause increases in temperature, heat rate, blood pressure and cortisol similar to those observed in conscious animal models (de la Torre et al, 2000).…”