The acute administration of MDMA has been shown to promote glycogenolysis and increase the extracellular concentration of glucose in the striatum. In the present study the role of 5-HT and/or NE pathways in the MDMA induced increase in extracellular glucose and glycogenolysis was assessed. The relationship of this response to MDMA induced hyperthermia also was determined. The administration of MDMA (10mg/kg, ip) resulted in a significant and sustained increase (50-100%) in the extracellular concentration of glucose not only in the striatum but also in the prefrontal cortex and hippocampus without altering peripheral blood glucose concentrations. Treatment of rats with fluoxetine (10mg/kg, ip) significantly attenuated the MDMA induced increase in extracellular glucose in the striatum but had no effect on MDMA induced hyperthermia or glycogenolysis. Treatment with prazosin (1mg/kg, ip) did not alter the glucose or glycogen responses to MDMA but completely suppressed the MDMA induced hyperthermia. Finally, propranolol (3mg/kg, ip) significantly attenuated the MDMA induced increase in extracellular glucose and glycogenolysis but did not alter MDMA induced hyperthermia. The present results suggest that MDMA increases extracellular glucose in multiple brain regions, and that this response involves both 5HT and NE mechanisms. Furthermore, beta adrenergic and alpha adrenergic receptors appear to contribute to MDMA-induced glycogenolysis and hyperthermia, respectively. Finally, hyperthermia, glycogenolysis and elevated extracellular glucose appear to be independent unrelated responses to acute MDMA administration.