Mitochondrial oxidant stress mediates methamphetamine neurotoxicity in substantia nigra dopaminergic neurons

Steven M. Graves, Sarah E. Schwarzschild, Rex A. Tai, Yu Chen, D. James Surmeier

Research output: Contribution to journalArticlepeer-review

Abstract

Methamphetamine abuse is associated with an increased risk of developing Parkinson's disease (PD). Recently, it was found that methamphetamine increases mitochondrial oxidant stress in substantia nigra pars compacta (SNc) dopaminergic neurons by releasing vesicular dopamine (DA) and stimulating mitochondrially-anchored monoamine oxidase (MAO). As mitochondrial oxidant stress is widely thought to be a driver of SNc degeneration in PD, these observations provide a potential explanation for the epidemiological linkage. To test this hypothesis, mice were administered methamphetamine (5 mg/kg) for 28 consecutive days with or without pretreatment with an irreversible MAO inhibitor. Chronic methamphetamine administration resulted in the degeneration of SNc dopaminergic neurons and this insult was blocked by pretreatment with a MAO inhibitor – confirming the linkage between methamphetamine, MAO and SNc degeneration. To determine if shorter bouts of consumption were as damaging, mice were given methamphetamine for two weeks and then studied. Methamphetamine treatment elevated both axonal and somatic mitochondrial oxidant stress in SNc dopaminergic neurons, was associated with a modest but significant increase in firing frequency, and caused degeneration after drug cessation. While axonal stress was sensitive to MAO inhibition, somatic stress was sensitive to Cav1 Ca2+ channel inhibition. Inhibiting either MAO or Cav1 Ca2+ channels after methamphetamine treatment attenuated subsequent SNc degeneration. Our results not only establish a mechanistic link between methamphetamine abuse and PD, they point to pharmacological strategies that could lessen PD risk for patients with a methamphetamine use disorder.

Original languageEnglish (US)
Article number105409
JournalNeurobiology of Disease
Volume156
DOIs
StatePublished - Aug 2021

Bibliographical note

Funding Information:
This work was supported by the JPB Foundation and MJFF (DJS), National Institutes of Health ( DA039253 , DA051450 ; SMG), and the Northwestern Memorial Foundation (SMG).

Publisher Copyright:
© 2021

Keywords

  • Degeneration
  • Dopamine
  • Methamphetamine
  • Mitochondrial stress
  • Monoamine oxidase
  • Parkinson's disease

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