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

Background 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 ( IP 3) 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 IP 3 inhibitor xestospongin C (0 to 0.5  μ M) or σ ‐1 receptor antagonist BD ‐1047 (0 to 80  μ M). Hippocampal viability was assessed via immunohistochemical labeling of neuron‐specific nuclear protein (NeuN)/Fox‐3 in CA 1, CA 3, 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 CA 1 subregion and significantly attenuated these effects in the CA 3 and DG regions. Xestospongin application also significantly increased NeuN/Fox‐3 immunofluorescence in EtOH‐naïve hippocampi. Co‐exposure to 20  μ M BD ‐1047 also reversed the loss of NeuN/Fox‐3 during CIE exposure in each hippocampal cell layer, whereas exposure to 80  μ M BD ‐1047 did not alter NeuN/Fox‐3 in EtOH‐treated hippocampi. By contrast, 80  μ M BD ‐1047 application significantly increased NeuN/Fox‐3 immunofluorescence in EtOH‐naïve hippocampi in each subregion. Conclusions These data suggest that EtOH stimulates ER IP 3 and σ ‐1 receptors to promote hippocampal loss of NeuN/Fox‐3 during CIE .