Methamphetamine-induced spectrin proteolysis in the rat striatum

Robert D. Staszewski, Bryan K. Yamamoto

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Methamphetamine (METH) is a widely abused psychostimulant. Multiple high doses of METH cause long-term toxicity to dopamine (DA) and serotonin (5-HT) nerve terminals in the brain, as evidenced by decreases in DA and 5-HT content, decreases in tyrosine and tryptophan hydroxylase activities, decreases in DA and 5-HT re-uptake sites, and nerve terminal degeneration. Multiple high doses of METH are known to elicit a rapid increase in DA release and hyperthermia. Although METH also produces a delayed and sustained rise in glutamate, no studies have shown whether METH produces structural evidence of excitotoxicity in striatum, or identified the receptors that mediate this toxicity directly, independent of alterations in METH-induced hyperthermia. These experiments investigated whether METH can cause excitotoxicity as evidenced by cytoskeletal protein breakdown in a glutamate receptor-dependent manner. METH increased calpain-mediated spectrin proteolysis in the rat striatum 5 and 7 days after METH administration without affecting caspase 3-dependent spectrin breakdown. This effect was completely blocked with the α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptor antagonist, GYKI 52466, but not the NMDA receptor antagonist, MK-801. However, AMPA or NMDA receptor antagonism did not attenuate the METH-induced depletions of the dopamine transporter (DAT). Independent mechanisms involved in mediating spectrin proteolysis and DAT protein loss are discussed.

Original languageEnglish (US)
Pages (from-to)1267-1276
Number of pages10
JournalJournal of Neurochemistry
Volume96
Issue number5
DOIs
StatePublished - Mar 1 2006
Externally publishedYes

Keywords

  • Calpain
  • Excitotoxicity
  • Glutamate
  • Methamphetamine
  • Spectrin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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