Long-Term Ethanol and Corticosterone Co-Exposure Sensitize the Hippocampal CA1 Region Pyramidal Cells to Insult During Ethanol Withdrawal in an NMDA GluN2B Subunit-Dependent Manner.

Background Chronic ethanol ( Et 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 Et 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 Et 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 Et OH exposure (50 mM) and 1 day of EWD. Et 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 Et OH exposure and EWD. Cytotoxicity (uptake of propidium iodide) was assessed in the pyramidal cell layer of the CA1 region. Western blot analysis was employed to assess the density of GluN2B subunits following Et OH and CORT exposure. Results EWD did not produce overt neurotoxicity. However, co-exposure to Et OH/ EWD and CORT produced significant neurotoxicity in the CA1 region pyramidal cell layer. Ifenprodil, a GluN2B polyamine site antagonist, significantly reduced toxicity from Et 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 Et 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. [ABSTRACT FROM AUTHOR]