The possibility that MDMA might serve as a bioenergetic stressor was investigated in rats by measuring rate of glycogenolysis and concentration of extracellular glucose after MDMA (10, 20 or 40 mg/kg given s.c.). Tissue glycogen and glucose were measured via fluorescence assay in brains usually removed 1 h after MDMA (except in time course study). Microdialysis studies measured extracellular glucose after MDMA administration. MDMA dose-dependently induced glycogenolysis, with the greatest increase seen after the 40 mg/kg dose. Extracellular striatal glucose increased immediately after MDMA, and remained elevated for 5 h afterwards. Central perfusion with 100 mM MDMA for 5 h by reverse dialysis did not increase extracellular glucose. Placement in cooler (17 C) room attenuated MDMA-induced glycogenolysis. Pre-treatment with the norepinephrine uptake inhibitor desipramine completely abolished glycogenolysis, and both 3 mg/kg LY-53857 (5HT2 antagonist) and 10 mg/kg iprindole (tricyclic antidepressant) attenuated glycogenolysis, where none of the above pre-treatments reduced glycogenolysis when given alone. LY-53857 also reduced MDMA-induced hyperthermia. Other studies in rats indicate that glycogenolysis also occurs after methamphetamine and PCA, but not after the serotonin releaser fenfluramine. In vitro studies have found a relationship between MDMA and glycogenolysis; this is the first in vivo study demonstrating that MDMA increases glucose use. While the authors interpret glycogenolysis as a measure of bioenergetic stress, it is also possible that increased glucose use arises directly from behavioral or pharmacological effects of MDMA that demand increased use of energy, such as increased locomotion or repeated transport of MDMA by the serotonin transporter. The authors did not measure the degree of serotoninergic neurotoxicity in their animals. Hence, they fail to present a direct link between glycogenolysis in this study and MDMA-induced neurotoxicity.