PMID- 25666033
OWN - NLM
STAT- MEDLINE
DCOM- 20160101
LR  - 20191210
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 93
DP  - 2015 Jun
TI  - Contribution of dopamine to mitochondrial complex I inhibition and dopaminergic 
      deficits caused by methylenedioxymethamphetamine in mice.
PG  - 124-33
LID - S0028-3908(15)00041-6 [pii]
LID - 10.1016/j.neuropharm.2015.01.025 [doi]
AB  - Methylenedioxymethamphetamine (MDMA) causes a persistent loss of dopaminergic 
      cell bodies in the substantia nigra of mice. Current evidence indicates that 
      MDMA-induced neurotoxicity is mediated by oxidative stress probably due to the 
      inhibition of mitochondrial complex I activity. In this study we investigated the 
      contribution of dopamine (DA) to such effects. For this, we modulated the 
      dopaminergic system of mice at the synthesis, uptake or metabolism levels. 
      Striatal mitochondrial complex I activity was decreased 1 h after MDMA; an effect 
      not observed in the striatum of DA depleted mice or in the hippocampus, a 
      dopamine spare region. The DA precursor, L-dopa, caused a significant reduction 
      of mitochondrial complex I activity by itself and exacerbated the dopaminergic 
      deficits when combined with systemic MDMA. By contrast, no damage was observed 
      when L-dopa was combined with intrastriatal injections of MDMA. On the other 
      hand, dopamine uptake blockade using GBR 12909, inhibited both, the acute 
      inhibition of complex I activity and the long-term dopaminergic toxicity caused 
      by MDMA. Moreover, the inhibition of DA metabolism with the monoamine oxidase 
      (MAO) inhibitor, pargyline, afforded a significant protection against 
      MDMA-induced complex I inhibition and neurotoxicity. Taken together, these 
      findings point to the formation of hydrogen peroxide subsequent to DA metabolism 
      by MAO, rather than a direct DA-mediated mitochondrial complex I inhibition, and 
      the contribution of a peripheral metabolite of MDMA, as the key steps in the 
      chain of biochemical events leading to DA neurotoxicity caused by MDMA in mice.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Barros-Minones, L
AU  - Barros-Minones L
AD  - Department of Pharmacology and Toxicology, School of Medicine, University of 
      Navarra, Spain.
FAU - Goni-Allo, B
AU  - Goni-Allo B
AD  - Department of Pharmacology and Toxicology, School of Medicine, University of 
      Navarra, Spain.
FAU - Suquia, V
AU  - Suquia V
AD  - Department of Pharmacology and Toxicology, School of Medicine, University of 
      Navarra, Spain.
FAU - Beitia, G
AU  - Beitia G
AD  - Department of Pharmacology and Toxicology, School of Medicine, University of 
      Navarra, Spain.
FAU - Aguirre, N
AU  - Aguirre N
AD  - Department of Pharmacology and Toxicology, School of Medicine, University of 
      Navarra, Spain.
FAU - Puerta, E
AU  - Puerta E
AD  - Department of Pharmacology and Toxicology, School of Medicine, University of 
      Navarra, Spain. Electronic address: epuerta@alumni.unav.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150207
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Dopamine Agents)
RN  - 0 (Hallucinogens)
RN  - 0 (Piperazines)
RN  - 102-32-9 (3,4-Dihydroxyphenylacetic Acid)
RN  - 46627O600J (Levodopa)
RN  - 658-48-0 (alpha-Methyltyrosine)
RN  - 67469-57-2 (1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - EC 4.2.1.3 (Aconitate Hydratase)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - VTD58H1Z2X (Dopamine)
RN  - X77S6GMS36 (Homovanillic Acid)
SB  - IM
MH  - 3,4-Dihydroxyphenylacetic Acid/metabolism
MH  - Aconitate Hydratase/metabolism
MH  - Animals
MH  - Body Temperature/drug effects
MH  - Corpus Striatum/drug effects/metabolism
MH  - Dopamine/*deficiency
MH  - Dopamine Agents/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Electron Transport Complex I/*metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Hallucinogens/*pharmacology
MH  - Homovanillic Acid/metabolism
MH  - Levodopa/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology
MH  - Piperazines/pharmacology
MH  - Tyrosine 3-Monooxygenase/metabolism
MH  - alpha-Methyltyrosine/pharmacology
OTO - NOTNLM
OT  - Complex I
OT  - Dopamine
OT  - MDMA
OT  - Mitochondria
OT  - Oxidative stress
EDAT- 2015/02/11 06:00
MHDA- 2016/01/02 06:00
CRDT- 2015/02/11 06:00
PHST- 2014/07/25 00:00 [received]
PHST- 2014/12/19 00:00 [revised]
PHST- 2015/01/27 00:00 [accepted]
PHST- 2015/02/11 06:00 [entrez]
PHST- 2015/02/11 06:00 [pubmed]
PHST- 2016/01/02 06:00 [medline]
AID - S0028-3908(15)00041-6 [pii]
AID - 10.1016/j.neuropharm.2015.01.025 [doi]
PST - ppublish
SO  - Neuropharmacology. 2015 Jun;93:124-33. doi: 10.1016/j.neuropharm.2015.01.025. 
      Epub 2015 Feb 7.