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On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serot

On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serot

  1. Jatelka
    Neuropharmacology. 2008 Apr;54(5):885-900

    Goñi-Allo B (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Puerta E (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Mathúna BO (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Hervias I (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Lasheras B (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), de la Torre R (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Aguirre N (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus)

    The mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonergic (5-HT) toxicity remain unclear. It has been suggested that MDMA depletes 5-HT by increasing brain tyrosine levels, which via non-enzymatic hydroxylation leads to DA-derived free radical formation. Because this hypothesis assumes the pre-existence of hydroxyl radicals, we hypothesized that MDMA metabolism into pro-oxidant compounds is the limiting step in this process. Acute hyperthermia, plasma tyrosine levels and concentrations of MDMA and its main metabolites were higher after a toxic (15mg/kg i.p.) vs. a non-toxic dose of MDMA (7.5mg/kg i.p.). The administration of a non-toxic dose of MDMA in combination with l-tyrosine (0.2mmol/kg i.p.) produced a similar increase in serum tyrosine levels to those found after a toxic dose of MDMA; however, brain 5-HT content remained unchanged. The non-toxic dose of MDMA combined with a high dose of tyrosine (0.5mmol/kg i.p.), caused long-term 5-HT depletions in rats treated at 21.5 degrees C but not in those treated at 15 degrees C, conditions known to decrease MDMA metabolism. Furthermore, striatal perfusion of MDMA (100muM for 5h) combined with tyrosine (0.5mmol/kg i.p.) in hyperthermic rats did not cause 5-HT depletions. By contrast, rats treated with the non-toxic dose of MDMA under heating conditions or combined with entacapone or acivicin, which interfere with MDMA metabolism or increase brain MDMA metabolite availability respectively, showed significant reductions of brain 5-HT content. Altogether, these data indicate that although tyrosine may contribute to MDMA-induced toxicity, MDMA metabolism appears to be the limiting step.

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