PMID- 18329670
OWN - NLM
STAT- MEDLINE
DCOM- 20080717
LR  - 20151119
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 54
IP  - 5
DP  - 2008 Apr
TI  - On the role of tyrosine and peripheral metabolism in 
      3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats.
PG  - 885-900
LID - 10.1016/j.neuropharm.2008.01.007 [doi]
AB  - 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.
FAU - Goni-Allo, Beatriz
AU  - Goni-Allo B
AD  - Department of Pharmacology, School of Medicine, University of Navarra, c/ 
      Irunlarrea 1, 31008 Pamplona, Spain.
FAU - Puerta, Elena
AU  - Puerta E
FAU - Mathuna, Brian O
AU  - Mathuna BO
FAU - Hervias, Isabel
AU  - Hervias I
FAU - Lasheras, Berta
AU  - Lasheras B
FAU - de la Torre, Rafael
AU  - de la Torre R
FAU - Aguirre, Norberto
AU  - Aguirre N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080203
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Antimetabolites)
RN  - 0 (Catechols)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Isoxazoles)
RN  - 0 (Nitriles)
RN  - 333DO1RDJY (Serotonin)
RN  - 42HK56048U (Tyrosine)
RN  - 4975G9NM6T (entacapone)
RN  - 54-16-0 (Hydroxyindoleacetic Acid)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - O0X60K76I6 (acivicin)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Antimetabolites/pharmacology
MH  - Area Under Curve
MH  - Body Temperature/drug effects
MH  - Brain/*drug effects/metabolism/pathology
MH  - Catechols/pharmacology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Enzyme Inhibitors/pharmacology
MH  - Hydroxyindoleacetic Acid/metabolism
MH  - Isoxazoles/pharmacology
MH  - Male
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neurotoxicity Syndromes/etiology/*metabolism
MH  - Nitriles/pharmacology
MH  - Protein Binding/drug effects
MH  - Rats
MH  - Rats, Wistar
MH  - Serotonin/*metabolism
MH  - Time Factors
MH  - Tyrosine/*metabolism/pharmacology
EDAT- 2008/03/11 09:00
MHDA- 2008/07/18 09:00
CRDT- 2008/03/11 09:00
PHST- 2007/07/05 00:00 [received]
PHST- 2008/01/11 00:00 [revised]
PHST- 2008/01/24 00:00 [accepted]
PHST- 2008/03/11 09:00 [pubmed]
PHST- 2008/07/18 09:00 [medline]
PHST- 2008/03/11 09:00 [entrez]
AID - S0028-3908(08)00031-2 [pii]
AID - 10.1016/j.neuropharm.2008.01.007 [doi]
PST - ppublish
SO  - Neuropharmacology. 2008 Apr;54(5):885-900. doi: 10.1016/j.neuropharm.2008.01.007. 
      Epub 2008 Feb 3.