On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats.
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 (15 mg/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 (0.2 mmol/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 (0.5 mmol/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 (100 microM for 5h) combined with tyrosine (0.5 mmol/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.
Goñi-Allo
Beatriz
B
Department of Pharmacology, School of Medicine, University of Navarra, c/ Irunlarrea 1, 31008 Pamplona, Spain.
Puerta
Elena
E
Mathúna
Brian O
BO
Hervias
Isabel
I
Lasheras
Berta
B
de la Torre
Rafael
R
Aguirre
Norberto
N
D000704:Analysis of Variance; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019540:Area Under Curve; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002396:Catechols / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism* / Q000494:pharmacology
D000963:Antimetabolites; D002396:Catechols; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D009570:Nitriles; D012701:Serotonin; D014443:Tyrosine; C071192:entacapone; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C006303:acivicin