Methamphetamine-induced inhibition of mitochondrial complex II: roles of glutamate and peroxynitrite.
High-dose methamphetamine (METH) is associated with long-term deficits in dopaminergic systems. Although the mechanism(s) which contributes to these deficits is not known, glutamate and peroxynitrite are likely to play a role. These factors are hypothesized to inhibit mitochondrial function, increasing the free radical burden and decreasing neuronal energy supplies. Previous studies suggest a role for the mitochondrial electron transport chain (ETC) in mediating toxicity of METH. The purpose of the present studies was to determine whether METH administration selectively inhibits complex II of the ETC in rats. High-dose METH administration (10 mg/kg every 2 h x 4) rapidly (within 1 h) decreased complex II (succinate dehydrogenase) activity by approximately 20-30%. In addition, decreased activity of complex II-III, but not complex I-III, of the mitochondrial ETC was also observed 24 h after METH. This inhibition was not due to direct inhibition by METH or METH-induced hyperthermia and was specific to striatal brain regions. METH-induced decreases in complex II-III were prevented by MK-801 and the peroxynitrite scavenger 5,10,15,20-tetrakis (2,4,6-trimethyl-3,5-sulphonatophenyl) porphinato iron III. These findings provide the first evidence that METH administration, via glutamate receptor activation and peroxynitrite formation, selectively alters a specific site of the ETC.
Brown
Jeffrey M
JM
Department of Pharmacology and Experimental Therapeutics, Laboratory of Neurochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Quinton
Maria S
MS
Yamamoto
Bryan K
BK
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D013385:Succinate Dehydrogenase / Q000378:metabolism
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D030421:Peroxynitrous Acid; D018698:Glutamic Acid; D008694:Methamphetamine; D019001:Nitric Oxide Synthase; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase