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Development of an In-vitro Model for Examining the Thermogenic Mechanisms of Ecstasy

Bryan Lizza, Patrick Symmonds

The illicit drug Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is associated with potentially life-threatening hyperthermia. Although previous MDMA studies have utilized animal models, our lab is developing an in-vitro model to determine the drug-induced thermogenesis. We are investigating second-messenger mediated responses that occur after MDMA administration. These mediators, which include free fatty acids (FFAs) and norepinephrine (NE), are hypothesized to activate mitochondrial uncoupling protein-3 (UCP3). UCP3 activation disrupts the proton gradient created by the electron transport chain (ETC). Normally, the proton gradient is used to couple the released stored energy to ATP production. However, when UCPs are activated, this free energy is released as heat (thermogenesis). Without the proton gradient, the cells must synthesize ATP by other means. Increased glucose uptake occurs secondary to ETC compromise because of the increased demand on other pathways to synthesize ATP. Skeletal muscle cells will be treated with FFA, NE, MDMA, both NE/FFA or 2,4-dinitrophenol, which is a known uncoupler. Cellular glucose uptake will be measured to determine the degree of uncoupling that occurred with each agent. After treatment, cortisol will be used to expel intracellular glucose. The amount of intracellular glucose released from the cells will be measured using blood glucose testing supplies.