2-deoxy-D-glucose prevents and nicotinamide potentiates 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity

Neurotoxicity induced by different substituted amphetamines has been associ ated with the exhaustion of intracellular energy stores. Accordingly, we ex amined the influence of 2-deoxy-D-glucose (2-DG), a competitive inhibitor o f glucose uptake and metabolism, and nicotinamide, an agent that improves e nergy metabolism, on 3,4-methylenedioxymethamphetamine (MDMA)-induced 5-hyd roxytryptamine (5-HT; serotonin) deficits. Administration of MDMA (15 mg/kg i.p,) produced a significant hyperthermia, whereas 2-DG caused a profound hypothermia that lasted throughout the experiment. When MDMA was given to 2 -DG-treated rats, an immediate but transient: hyperthermia occurred and was followed by a return to hypothermia. 2-DG had no effect on 5-HT concentrat ions in the frontal cortex, hippocampus, and striatum but prevented the neu rotoxicity induced by MDMA. When rats were injected with 2-DG/MDMA and were warmed to prevent hypothermia, the protection afforded by 2-DG was abolish ed. Nicotinamide had no effect on body temperature of the rats, and the hyp erthermia induced by the nicotinamide/MDMA treatment was similar to that of the saline/MDMA-treated rats. However, the long-term 5-HT deficits induced by MDMA were potentiated by nicotinamide in all the brain regions examined . Finally, no change on ATP concentrations in the frontal cortex, hippocamp us, and striatum was observed up to 3 h after a single dose of MDMA. These results suggest that an altered energy metabolism is not the main cause of the neurotoxic effects induced by MDMA.