Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades

FASEB J. 2004 Feb;18(2):238-51. doi: 10.1096/fj.03-0295com.


Methamphetamine (METH) is an illicit drug that causes neurodegenerative effects in humans. In rodents, METH induces apoptosis of striatal glutamic acid decarboxylase (GAD) -containing neurons. This paper provides evidence that METH-induced cell death occurs consequent to interactions of ER stress and mitochondrial death pathways. Specifically, injections of METH are followed by an almost immediate activation of proteases calpain and caspase-12, events consistent with drug-induced ER stress. Involvement of ER stress was further supported by observations of increases in the expression of GRP78/BiP and CHOP. Participation of the mitochondrial pathway was demonstrated by the transition of AIF, smac/DIABLO, and cytochrome c from mitochondrial into cytoplasmic fractions. These changes occur before the apoptosome-associated pro-caspase-9 cleavage. Effector caspases-3 and -6, but not -7, were cleaved with the initial time of caspase-3 activation occurring before caspase 9 cleavage; this suggests possible earlier cleavage of caspase-3 by caspase-12. These events preceded proteolysis of the caspase substrates DFF-45, lamin A, and PARP in nuclear fractions. These findings indicate that METH causes neuronal apoptosis in part via cross-talks between ER- and mitochondria-generated processes, which cause activation of both caspase-dependent and -independent pathways.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Calpain / metabolism
  • Carrier Proteins / genetics
  • Caspases / metabolism
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation / drug effects
  • Heat-Shock Proteins*
  • Male
  • Methamphetamine / pharmacology*
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Models, Biological
  • Molecular Chaperones / genetics
  • Neostriatum / cytology
  • Neurons / cytology*
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neurons / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • gamma-Aminobutyric Acid / pharmacology


  • Carrier Proteins
  • Heat-Shock Proteins
  • Molecular Chaperones
  • RNA, Messenger
  • Methamphetamine
  • gamma-Aminobutyric Acid
  • Calpain
  • Caspases
  • molecular chaperone GRP78