Neurotoxic effects of chronic restraint stress in the striatum of methamphetamine-exposed rats

M. S. Quinton, B. K. Yamamoto

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Rationale: Stress is a common experience in drug abusers. Methamphetamine (METH) is an abused psychostimulant that damages dopamine and serotonin terminals through pro-oxidant mechanisms and glutamate-mediated excitotoxicity. Both METH and stress increase dopamine and glutamate release in the striatum. Since dopamine inhibits striatal glutamate release and METH depletes dopamine, stress-induced glutamate release may be disinhibited after METH exposure. Objective: We examined if repeated stress would worsen excitotoxic damage to the striatum after METH pretreatment. Materials and methods: In vivo microdialysis was used to examine stress-induced striatal glutamate release in rats pre-exposed to METH (7.5 mg/kg × 4 injections) or saline. The effects on striatal DA, serotonin, DAT, SERT, and spectrin proteolysis produced by chronic restraint stress (CRS, 6 h/day for 21 days) in the presence or absence of corticosterone synthesis inhibition by metyrapone (50 mg/kg) beginning 7 days after METH were also examined. Results: Stress-induced glutamate release was augmented in rats pre-exposed to METH. CRS 7 days after METH enhanced METH-induced DAT depletions from 23 to 44% in the nonstressed versus stressed rats, respectively. Striatal SERT and serotonin tissue content were decreased by 51 and 36%, respectively, in rats exposed to both METH and CRS but was unchanged by either treatment alone. Spectrin proteolysis was increased by 53% in rats treated with both METH and CRS but was unaffected by either treatment alone. Metyrapone blocked the effects of CRS on METH-induced depletions of SERT but not DAT. Conclusions: Exposure to chronic stress depleted striatal dopamine and serotonin terminal markers possibly through excitotoxic mechanisms in METH-treated rats.

Original languageEnglish (US)
Pages (from-to)341-350
Number of pages10
JournalPsychopharmacology
Volume193
Issue number3
DOIs
StatePublished - Aug 1 2007
Externally publishedYes

Keywords

  • Chronic restraint stress
  • Dopamine transporter
  • Excitotoxicity
  • Glutamate
  • Methamphetamine
  • Metyrapone
  • Serotonin transporter
  • Spectrin proteolysis

ASJC Scopus subject areas

  • Pharmacology

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