Inhibition of sigma-1 receptor reduces N-methyl-d-aspartate induced neuronal injury in methamphetamine-exposed and -naive hippocampi

Katherine J. Smith, Tracy R. Butler, Mark A. Prendergast

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Acute and prolonged methamphetamine (METH) exposure has been reported to moderate the function of N-methyl-d-aspartate type glutamate receptors (NMDAr) in the hippocampus. These effects have been found to be associated with enhanced NMDAr-dependent release of Ca2+ from IP3-sensitive intracellular stores. The present studies were designed to extend these findings and examine the role of the endoplasmic membrane (ER) bound orphan receptor, the sigma-1 receptor, in NMDA-induced neuronal injury and METH withdrawal-potentiated NMDA-induced neuronal injury. Organotypic hippocampal slice cultures were exposed to METH (0 or 100μM) for 6 days and withdrawn for 7 days, then exposed to NMDA (0 or 5μM) for 24h. Additional cultures were also exposed to this regimen and were co-incubated with BD1047 (100μM), a specific inhibitor of ER-bound sigma-1 receptors, for the 24h NMDA exposure. Cytotoxicity was assessed by analysis of propidium iodide uptake. These studies demonstrated that protracted METH exposure and withdrawal significantly potentiated the neuronal injury produced by NMDA exposure. Further, co-exposure to BD1047 with NMDA markedly attenuated neuronal injury in METH-naïve and METH-withdrawn organotypic cultures. As a whole, these data demonstrate that prolonged METH exposure, even at non-toxic concentrations, significantly alters glutamate receptor signaling. Inhibition of sigma-1 receptor-dependent Ca2+ release from the ER entirely prevented NMDA-induced toxicity in METH-naïve cultures and markedly reduced METH-potentiated toxicity. These findings demonstrate the importance of Ca2+-induced intracellular Ca2+ release in excitotoxic insult and suggest that blockade of glutamatergic overactivity may represent a therapeutic target in the treatment of METH withdrawal.

Original languageEnglish
Pages (from-to)144-148
Number of pages5
JournalNeuroscience Letters
Volume481
Issue number3
DOIs
StatePublished - Sep 2010

Keywords

  • Hippocampus
  • Methamphetamine
  • NMDA
  • Sigma-1 receptor

ASJC Scopus subject areas

  • General Neuroscience

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