Methamphetamine-induced inhibition of mitochondrial complex II: roles of glutamate and peroxynitrite

Area of Science:

• Neuroscience
• Biochemistry
• Toxicology

Background:

• High-dose methamphetamine (METH) causes long-term dopaminergic system deficits.
• Glutamate and peroxynitrite are implicated in METH-induced neurotoxicity by inhibiting mitochondrial function.
• The mitochondrial electron transport chain (ETC) is a potential target for METH toxicity.

Purpose of the Study:

• To investigate if METH administration selectively inhibits complex II of the mitochondrial ETC in rats.
• To elucidate the role of glutamate and peroxynitrite in METH-induced mitochondrial dysfunction.

Main Methods:

• Rats were administered high-dose METH (10 mg/kg every 2 h x 4).
• Mitochondrial ETC complex activities (specifically complex II, II-III, and I-III) were measured in striatal brain regions.
• The effects of MK-801 (glutamate receptor antagonist) and a peroxynitrite scavenger were assessed.

Main Results:

• METH rapidly decreased complex II (succinate dehydrogenase) activity by 20-30% within 1 hour.
• METH also decreased complex II-III activity, but not complex I-III, 24 hours post-administration.
• These METH-induced effects were specific to striatal regions and not caused by direct METH inhibition or hyperthermia.
• MK-801 and the peroxynitrite scavenger prevented the METH-induced decreases in complex II-III activity.

Conclusions:

• METH administration selectively inhibits complex II and complex II-III of the mitochondrial ETC in rats.
• Glutamate receptor activation and peroxynitrite formation mediate METH-induced mitochondrial dysfunction.
• These findings provide evidence for a specific mechanism underlying METH neurotoxicity affecting neuronal energy metabolism.