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TOXICOLOGY

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

Departments of Anesthesiology (W.K.), Applied Physiology (K.J.-R., F.L.-H.), and Forensic Medicine (A.A.), Ulm University, Ulm, Germany; Department of Biochemistry, University College Cork, Cork, Ireland (J.J.A.H., G.O.); and Department of Neurology, Hannover University, Hannover, Germany (F.S., J.B.)

Adverse 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) effects are usually ascribed to neurotransmitter release in the central nervous system. Since clinical features such as fasciculations, muscle cramps, rapidly progressing hyperthermia, hyperkalemia, and rhabdomyolysis point to the skeletal muscle as additional target, we studied the effects of MDMA on native and cultured skeletal muscle. We addressed the question whether malignant hyperthermia (MH)-susceptible (MHS) muscle is predisposed to adverse MDMA reactions. Force measurements on muscle strips showed that 100 µM MDMA, a concentration close to that determined in some MDMA users, regularly enhanced the sensitivity of skeletal muscle to caffeine-induced contractures but did not cause contractures on its own. The left-shift of the dose-response curve induced by MDMA was greater in normal than in MHS muscle. Furthermore, MDMA did not release Ca²⁺ from isolated sarcoplasmic reticulum vesicles. These findings do not support the view of an MH-triggering effect on muscle. However, MDMA induced Ca²⁺ transients in myotubes and increased their acidification rate. Surprisingly, -bungarotoxin, a specific antagonist of the nicotinic acetylcholine receptor (nAChR), abolished these MDMA effects. The nAChR agonistic action of MDMA was confirmed by patch-clamp measurements of ion currents on human embryonic kidney cells expressing nAChR. We conclude that the neuromuscular junction is a target of MDMA and that an activation of nAChR contributes to the muscle-related symptoms of MDMA users. The drug may be of particular risk in individuals with abundant extrajunctional nAChR such as in generalized denervation or muscle regeneration processes and may act on central nAChR.

Address correspondence to: Dr. Frank Lehmann-Horn, Department of Applied Physiology, Ulm University, Albert-Einstein-Allee 11, 89069 Ulm, Germany. E-mail: frank.lehmann-horn{at}medizin.uni-ulm.de

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