title: Ethanol Stimulates Endoplasmic Reticulum Inositol Triphosphate and Sigma Receptors to Promote Withdrawal-Associated Loss of Neuron-Specific Nuclear Protein/Fox-3.
abstract: Prior studies demonstrate that ethanol (EtOH) exposure induces the release of intracellular calcium (CA(2+) ) 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 CA(2+) released from endoplasmic reticulum (ER)-bound inositol triphosphate (IP3) and σ-1 receptors in regulating hippocampal function has yet to be delineated.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These data suggest that EtOH stimulates ER IP3 and σ-1 receptors to promote hippocampal loss of NeuN/Fox-3 during CIE.
authors.affiliation: Department of Behavioral Science, University of Kentucky, Lexington, Kentucky.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Reynolds
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, Kentucky.|Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Saunders
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, Kentucky.|Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Prendergast
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; D005029:Ethylenediamines; D007295:Inositol Phosphates; D047028:Macrocyclic Compounds; D009419:Nerve Tissue Proteins; D010080:Oxazoles; C546339:Rbfox3 protein, rat; D017480:Receptors, sigma; C511704:xestospongin C; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D000431:Ethanol; C092449:inositol 1,2,3-trisphosphate
keywords: Calcium; Ethanol Withdrawal; Inositol Triphosphate; Neuron-Specific Nuclear Protein; Sigma-1