title: Contribution of dopamine to mitochondrial complex I inhibition and dopaminergic deficits caused by methylenedioxymethamphetamine in mice.
abstract: 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.
authors: Department of Pharmacology and Toxicology, School of Medicine, University of Navarra, Spain.
authors: L
authors: L
authors: Barros-Miñones
authors: Department of Pharmacology and Toxicology, School of Medicine, University of Navarra, Spain.
authors: B
authors: B
authors: Goñi-Allo
authors: Department of Pharmacology and Toxicology, School of Medicine, University of Navarra, Spain.
authors: V
authors: V
authors: Suquia
authors: Department of Pharmacology and Toxicology, School of Medicine, University of Navarra, Spain.
authors: G
authors: G
authors: Beitia
authors: Department of Pharmacology and Toxicology, School of Medicine, University of Navarra, Spain.
authors: N
authors: N
authors: Aguirre
authors: Department of Pharmacology and Toxicology, School of Medicine, University of Navarra, Spain. Electronic address: epuerta@alumni.unav.es.
authors: E
authors: E
authors: Puerta
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000172:deficiency*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006213:Hallucinogens / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D019805:alpha-Methyltyrosine / Q000494:pharmacology
chemical_list: D015259:Dopamine Agents; D006213:Hallucinogens; D010879:Piperazines; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D019805:alpha-Methyltyrosine; C039737:1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine; D014446:Tyrosine 3-Monooxygenase; D000154:Aconitate Hydratase; D042967:Electron Transport Complex I; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Complex I; Dopamine; MDMA; Mitochondria; Oxidative stress