Ethanol Stimulates Endoplasmic Reticulum Inositol Triphosphate and Sigma Receptors to Promote Withdrawal-Associated Loss of Neuron-Specific Nuclear Protein/Fox-3

Anna R. Reynolds, Meredith A. Saunders, Mark A. Prendergast

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Background: Prior studies demonstrate that ethanol (EtOH) exposure induces the release of intracellular calcium (CA2+) in modulation of γ-aminobutyric acid-ergic tone and produces concomitant alterations in sigma (σ)-1 protein expression that may contribute to the development EtOH dependence. However, the influence of CA2+ released from endoplasmic reticulum (ER)-bound inositol triphosphate (IP3) and σ-1 receptors in regulating hippocampal function has yet to be delineated. Methods: Rat hippocampal explants were subjected to chronic intermittent EtOH (CIE) exposure with or without the addition of IP3 inhibitor xestospongin C (0 to 0.5 μM) or σ-1 receptor antagonist BD-1047 (0 to 80 μM). Hippocampal viability was assessed via immunohistochemical labeling of neuron-specific nuclear protein (NeuN)/Fox-3 in CA1, CA3, and dentate gyrus (DG) subregions. Results: Exposure to CIE produced consistent and significant decreases of NeuN/Fox-3 in each primary cell layer of the hippocampal formation. Co-exposure to xestospongin reversed these effects in the CA1 subregion and significantly attenuated these effects in the CA3 and DG regions. Xestospongin application also significantly increased NeuN/Fox-3 immunofluorescence in EtOH-naïve hippocampi. Co-exposure to 20 μM BD-1047 also reversed the loss of NeuN/Fox-3 during CIE exposure in each hippocampal cell layer, whereas exposure to 80 μM BD-1047 did not alter NeuN/Fox-3 in EtOH-treated hippocampi. By contrast, 80 μM BD-1047 application significantly increased NeuN/Fox-3 immunofluorescence in EtOH-naïve hippocampi in each subregion. Conclusions: These data suggest that EtOH stimulates ER IP3 and σ-1 receptors to promote hippocampal loss of NeuN/Fox-3 during CIE.

Original languageEnglish
Pages (from-to)1454-1461
Number of pages8
JournalAlcoholism: Clinical and Experimental Research
Volume40
Issue number7
DOIs
StatePublished - Jul 1 2016

Bibliographical note

Publisher Copyright:
Copyright © 2016 by the Research Society on Alcoholism

Keywords

  • Calcium
  • Ethanol Withdrawal
  • Inositol Triphosphate
  • Neuron-Specific Nuclear Protein
  • Sigma-1

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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