Methamphetamine‐induced neurotoxicity: Roles for glutamate and dopamine efflux

Stacy E. Stephans, Bryan K. Yamamoto

Research output: Contribution to journalArticle

230 Scopus citations

Abstract

The neurotoxic effect of methamphetamine (METH) on striatal dopaminergic neurons have been hypothesized to be mediated by excess dopamine (DA) release. In addition, N‐methyl‐D‐aspartate (NMDA) receptor antagonists block METH‐induced DA depletions. This suggests that glutamate also mediates the toxic effects of METH. The purpose of this study is to demonstrate that DA and glutamate efflux contribute to METH‐inducted neurotoxicity. In vivo microdialysis in rats was used to measure extracellular concentrations of striatal DA and glutamate following 3 injections of METH (10 mg/kg, i.p.), each injection given 2 hours apart. One week following the dialysis experiment, rats were sacrificed and the ventral lateral striata were assayed for DA content. Glutamate concentrations in the dialysate increased by over 4‐fold after the third METH injection. In these same animals, striatal DA tissue content was significantly depleted. In separate groups of rats, pretreatment with haloperidol (2 mg/kg at the first METH injection) significantly increased METH‐induced DA efflux. The haloperidel pretreatment attenuated the extracellular increase in glutamate produced by METH and blocked subsequent neurotoxicity to DA neurons. In contrast, pretreatment with the DA uptake blocker, GBR‐12909 (10 mg/kg, 30 min before each METH injection) significantly attenuated the increased DA release produced by METH but did not change glutamate efflux. However, pretreatment with GBR‐12909 did protect against the tissue content depletion of DA in the striatum. Based on these findings, it appears that increased DA and glutamate release in the striatum are important and possibly interact in the development of METH‐induced neurotoxicity. © 1994 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)203-209
Number of pages7
JournalSynapse
Volume17
Issue number3
DOIs
StatePublished - Jul 1994
Externally publishedYes

Keywords

  • Dopamine
  • Glutamate
  • Methamphetamine
  • Microdialysis
  • Neurotoxicity
  • Striatum

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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