2-Deoxy-D-glucose prevents and nicotinamide potentiates 3, 4-methylenedioxymethamphetamine-induced serotonin neurotoxicity.
Neurotoxicity induced by different substituted amphetamines has been associated with the exhaustion of intracellular energy stores. Accordingly, we examined the influence of 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glucose uptake and metabolism, and nicotinamide, an agent that improves energy metabolism, on 3, 4-methylenedioxymethamphetamine (MDMA)-induced 5-hydroxytryptamine (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 concentrations in the frontal cortex, hippocampus, and striatum but prevented the neurotoxicity induced by MDMA. When rats were injected with 2-DG/MDMA and were warmed to prevent hypothermia, the protection afforded by 2-DG was abolished. Nicotinamide had no effect on body temperature of the rats, and the hyperthermia 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, hippocampus, 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.
Department of Pharmacology, University of Navarra Medical School, Pamplona, Spain.
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Hervías
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Lasheras
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Aguirre
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009419:Nerve Tissue Proteins; D009498:Neurotoxins / Q000633:toxicity; D009536:Niacinamide / Q000494:pharmacology*; D009928:Organ Specificity; D017374:Paroxetine / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D015102:3,4-Dihydroxyphenylacetic Acid; D009536:Niacinamide; D012701:Serotonin; D017374:Paroxetine; D006897:Hydroxyindoleacetic Acid; D000255:Adenosine Triphosphate; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D006719:Homovanillic Acid