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On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats.
Neuropharmacology. 2008 Apr; 54(5):885-900.N

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology, School of Medicine, University of Navarra, c/ Irunlarrea 1, 31008 Pamplona, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18329670

Citation

Goñi-Allo, Beatriz, et al. "On the Role of Tyrosine and Peripheral Metabolism in 3,4-methylenedioxymethamphetamine-induced Serotonin Neurotoxicity in Rats." Neuropharmacology, vol. 54, no. 5, 2008, pp. 885-900.
Goñi-Allo B, Puerta E, Mathúna BO, et al. On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats. Neuropharmacology. 2008;54(5):885-900.
Goñi-Allo, B., Puerta, E., Mathúna, B. O., Hervias, I., Lasheras, B., de la Torre, R., & Aguirre, N. (2008). On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats. Neuropharmacology, 54(5), 885-900. https://doi.org/10.1016/j.neuropharm.2008.01.007
Goñi-Allo B, et al. On the Role of Tyrosine and Peripheral Metabolism in 3,4-methylenedioxymethamphetamine-induced Serotonin Neurotoxicity in Rats. Neuropharmacology. 2008;54(5):885-900. PubMed PMID: 18329670.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats. AU - Goñi-Allo,Beatriz, AU - Puerta,Elena, AU - Mathúna,Brian O, AU - Hervias,Isabel, AU - Lasheras,Berta, AU - de la Torre,Rafael, AU - Aguirre,Norberto, Y1 - 2008/02/03/ PY - 2007/07/05/received PY - 2008/01/11/revised PY - 2008/01/24/accepted PY - 2008/3/11/pubmed PY - 2008/7/18/medline PY - 2008/3/11/entrez SP - 885 EP - 900 JF - Neuropharmacology JO - Neuropharmacology VL - 54 IS - 5 N2 - 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. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/18329670/On_the_role_of_tyrosine_and_peripheral_metabolism_in_34_methylenedioxymethamphetamine_induced_serotonin_neurotoxicity_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(08)00031-2 DB - PRIME DP - Unbound Medicine ER -