Vol. 301, Issue 1, 138-144, April 2002

3,4-Methylenedioxymethamphetamine Produces Glycogenolysis and Increases the Extracellular Concentration of Glucose in the Rat Brain

Altaf S. Darvesh, Mahalakshmi Shankaran and Gary A. Gudelsky

College of Pharmacy, University of Cincinnati, Cincinnati, Ohio

Oxidative and/or bioenergetic stress is thought to contribute to the mechanism of neurotoxicity of amphetamine derivatives, e.g., 3,4-methylenedioxymethamphetamine (MDMA). In the present study, the effect of MDMA on brain energy regulation was investigated by examining the effect of MDMA on brain glycogen and glucose. A single injection of MDMA (10-40 mg/kg, s.c.) produced a dose-dependent decrease (40%) in brain glycogen, which persisted for at least 1 h. MDMA (10 and 40 mg/kg, s.c.) also produced a significant and sustained increase in the extracellular concentration of glucose in the striatum. Subjecting rats to a cool ambient temperature of 17°C significantly attenuated MDMA-induced hyperthermia and glycogenolysis. MDMA-induced glycogenolysis also was prevented by treatment of rats with the 5-hydroxytryptamine₂ (5-HT₂) antagonists 6-methyl-1-(1-methylethyl)-ergoline-8-carboxylic acid 2-hydroxy-1 methylprophyl ester maleate (LY-53,857; 3 mg/kg i.p.), desipramine (10 mg/kg i.p.), and iprindole (10 mg/kg i.p.). LY-53,857 also attenuated the MDMA-induced increase in the extracellular concentration of glucose as well as MDMA-induced hyperthermia. Amphetamine analogs (e.g., methamphetamine and parachloroamphetamine) that produce hyperthermia also produced glycogenolysis, whereas fenfluramine, which does not produce hyperthermia, did not alter brain glycogen content. These results support the conclusion that MDMA induces glycogenolysis and that the process involves 5-HT₂ receptor activation. These results are supportive of the view that MDMA promotes energy dysregulation and that hyperthermia may play an important role in MDMA-induced alterations in cellular energetics.