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Long‐Term Ethanol and Corticosterone Co‐Exposure Sensitize the Hippocampal CA 1 Region Pyramidal Cells to Insult During Ethanol Withdrawal in an NMDA GluN2B Subunit‐Dependent Manner
Author(s) -
Butler Tracy R.,
Berry Jennifer N.,
SharrettField Lynda J.,
Pauly James R.,
Prendergast Mark A.
Publication year - 2013
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12195
Subject(s) - neurotoxicity , ifenprodil , nmda receptor , corticosterone , endocrinology , medicine , hippocampal formation , chemistry , toxicity , receptor , biology , biochemistry , hormone
Background Chronic ethanol ( E t OH ) exposure produces neuroadaptations in NMDA receptor function and/or abundance and alterations in hypothalamic–pituitary–adrenal ( HPA ) axis functioning that contribute to neuronal excitation and neurotoxicity during ethanol withdrawal ( EWD ). Both E t OH and corticosterone (CORT) promote synthesis of polyamines, which allosterically potentiate NMDA receptor function at the GluN2B subunit. The current studies investigated the effect of 10‐day E t OH and CORT co‐exposure on toxicity during EWD in rat hippocampal explants and hypothesized that alterations in function and/or density of GluN2B subunits contribute to the toxicity. Methods Organotypic hippocampal slice cultures were exposed to CORT (0.01–1.0 μM) during 10‐day E t OH exposure (50 mM) and 1 day of EWD . E t OH ‐naïve cultures were exposed to CORT for 11 days. Additional cultures were exposed to a membrane impermeable form of CORT ( BSA ‐ CORT ) with and without 10‐day E t OH exposure and EWD . Cytotoxicity (uptake of propidium iodide) was assessed in the pyramidal cell layer of the CA 1 region. Western blot analysis was employed to assess the density of GluN2B subunits following E t OH and CORT exposure. Results EWD did not produce overt neurotoxicity. However, co‐exposure to E t OH / EWD and CORT produced significant neurotoxicity in the CA 1 region pyramidal cell layer. Ifenprodil, a GluN2B polyamine site antagonist, significantly reduced toxicity from E t OH and CORT (0.1 μM) co‐exposure during EWD . However, Western blots did not reveal differences in GluN2B subunit density among groups. Exposure to BSA ‐ CORT did not produce toxicity, suggesting that membrane‐bound CORT receptors did not significantly contribute to the observed toxicity. Conclusions These data suggest that CORT and E t OH co‐exposure result in increased function of polyamine‐sensitive GluN2B subunits, but this toxicity does not appear dependent on the abundance of hippocampal NMDA GluN2B subunits or membrane‐bound CORT receptor function.