Chronic methamphetamine-induced neurodegeneration: Differential vulnerability of ventral tegmental area and substantia nigra pars compacta dopamine neurons

Yijuan Du, You Bin Lee, Steven M. Graves

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in substantia nigra pars compacta (SNc) axons; chronic administration produces SNc degeneration that is prevented by MAO inhibition suggesting that MAO-dependent axonal mitochondrial stress is a causal factor. To test whether meth similarly increases mitochondrial stress in ventral tegmental area (VTA) axons, we used a genetically encoded redox biosensor to assess mitochondrial stress ex vivo. Meth increased MAO-dependent mitochondrial stress in both SNc and VTA axons. However, despite having the same meth-induced stress as SNc neurons, VTA neurons were resistant to chronic meth-induced degeneration indicating that meth-induced MAO-dependent mitochondrial stress in axons was necessary but not sufficient for degeneration. To determine whether L-type Ca2+ channel-dependent stress differentiates SNc and VTA axons, as reported in the soma, the L-type Ca2+ channel activator Bay K8644 was used. Opening L-type Ca2+ channels increased axonal mitochondrial stress in SNc but not VTA axons. To first determine whether mitochondrial stress was necessary for SNc degeneration, mice were treated with the mitochondrial antioxidant mitoTEMPO. Chronic meth-induced SNc degeneration was prevented by mitoTEMPO thereby confirming the necessity of mitochondrial stress. Similar to results with the antioxidant, both MAO inhibition and L-type Ca2+ channel inhibition also prevented SNc degeneration. Taken together the presented data demonstrate that both MAO- and L-type Ca2+ channel-dependent mitochondrial stress is necessary for chronic meth-induced degeneration.

Original languageEnglish (US)
Article number108817
JournalNeuropharmacology
Volume200
DOIs
StatePublished - Dec 1 2021

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health Grants DA039253 , DA051450 , and AG070962 (to SMG) and DA048742 (to the University of Minnesota Viral Vector and Cloning Core ).

Publisher Copyright:
© Elsevier Ltd

Keywords

  • L-type Ca channel
  • Methamphetamine
  • Mitochondrial stress
  • Monoamine oxidase
  • Neurodegeneration
  • Substantia nigra pars compacta
  • Ventral tegmental area

Fingerprint

Dive into the research topics of 'Chronic methamphetamine-induced neurodegeneration: Differential vulnerability of ventral tegmental area and substantia nigra pars compacta dopamine neurons'. Together they form a unique fingerprint.

Cite this