Methamphetamine exposure antagonizes N-methyl-d-aspartate receptor-mediated neurotoxicity in organotypic hippocampal slice cultures

Katherine J. Smith, Rachel L. Self, Tracy R. Butler, Michael M. Mullins, Layla Ghayoumi, Robert C. Holley, John M. Littleton, Mark A. Prendergast

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Glutamatergic systems have been increasingly recognized as mediators of methamphetamine's (METH) pharmacological effects though little is known about the means by which METH interacts with glutamate receptors. The present studies examined effects of METH (0.1-100 μM) on [3H]MK-801 binding to membranes prepared from adult rat cortex, hippocampus and cerebellum, as well as the neurotoxicity produced by 24-h exposure to N-methyl-d-aspartate (5-10 μM; NMDA) employing organotypic hippocampal slice cultures of neonatal rat. Co-incubation of [3H]MK-801 with METH (0.1-100 μM) did not reduce dextromethorphan (1 mM)-displaceable ligand binding. Exposure of slice cultures to NMDA for 24-h produced increases in uptake of the non-vital fluorescent marker propidium iodide (PI) of 150-500% above control levels, most notably, in the CA1 region pyramidal cell layer. Co-exposure to METH (> 1.0 μM) with NMDA (5 μM) reduced PI uptake by approximately 50% in each subregion, though the CA1 pyramidal cell layer was markedly more sensitive to the protective effects of METH exposure. In contrast, METH exposure did not reduce PI uptake stimulated by 24-h exposure to 10 μM NMDA. Co-exposure to the NMDA receptor antagonist d-2-amino-5-phosphonovaleric acid (20 μM) prevented toxicity produced by exposure to 5 or 10 μM NMDA. These findings indicate that the pharmacological effects of short-term METH exposure involve inhibition of NMDA receptor-mediated neuronal signaling, not reflective of direct channel inhibition at an MK-801-sensitive site.

Original languageEnglish
Pages (from-to)74-80
Number of pages7
JournalBrain Research
Issue number1
StatePublished - Jul 9 2007


  • Amphetamine
  • Excitotoxicity
  • Glutamate
  • Hippocampus
  • Stimulants

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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