Contribution of dopamine to mitochondrial complex I inhibition and dopaminergic deficits caused by methylenedioxymethamphetamine in mice

• Published in: Neuropharmacology Vol. 93; pp. 124 - 133
• Main Authors: Barros-Miñones, L., Goñi-Allo, B., Suquia, V., Beitia, G., Aguirre, N., Puerta, E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2015
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Aconitate Hydratase - metabolism; alpha-Methyltyrosine - pharmacology; Animals; Body Temperature - drug effects; Complex I; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine; Dopamine - deficiency; Dopamine Agents - pharmacology; Dose-Response Relationship, Drug; Electron Transport Complex I - metabolism; Gene Expression Regulation - drug effects; Hallucinogens - pharmacology; Homovanillic Acid - metabolism; Levodopa - pharmacology; Male; MDMA; Mice; Mice, Inbred C57BL; Mitochondria; N-Methyl-3,4-methylenedioxyamphetamine - pharmacology; Oxidative stress; Piperazines - pharmacology; Tyrosine 3-Monooxygenase - metabolism; Oxidative stress; Mitochondria; Dopamine; TH; ROS; Complex I; MAO; DA; AMPT; MDMA
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.01.025

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. •DA presence is necessary for MDMA induced complex I inhibition and neurotoxicity in mice.•L-Dopa potentiates MDMA-induced dopaminergic deficits.•DA uptake inhibition reduces the neurotoxic effects of MDMA in mice.•A peripheral MDMA metabolite and DA metabolism are essential in MDMA neurotoxicity.