Fellowship Patrick Mulholland: Ethanol Withdrawal, Stress and Polyamine Neuroprotection

Grants and Contracts Details

Description

--The primary objective of this proposal is to test the hypothesis that: corticosterone exposure potentiates ethanol withdrawal (EWD)-induced toxicity. The primary aim of this proposal will be achieved by: 1. Determining the effects of corticosterone exposure during ethanol exposure and/or withdrawal from chronic ethanol exposure on toxicity utilizing organotypic hippocampal slice cultures from neonatal rat brain. The aim of this set of experiments was to characterize the effects of corticosterone (CORT) exposure during the withdrawal period from la-day ethanol exposure. We chose an ethanol treatment regiment that itself does not cause significant cytotoxicity upon withdrawal (i.e. 50 roM) and non-toxic CORT concentrations. When CORT was exposed to cultures at the initiation of ethanol withdrawal, a concentration-dependent effect was observed. In the CA1 region, 0.1 uM CORT increased cytotoxicity above control cultures and cultures withdrawn from la-day ethanol exposure. In cultures treated with 1.0 uM CORT during the withdrawal period, a significant increase in cytotoxicity was observed above cultures treated with 0.1 uM CORT during EWD. In addition, 1.0 uM CORT exposure during EWD resulted in significant cytotoxicity in the dentate gyrus, an effect that was not observed at any other CORT concentration or in cultures withdrawn from ethanol. An attenuation of cytotoxicity induced by CORT and EWD was observed in cultures treated with 20 uM MK-B01 during the withdrawal period. In the final set of experiments, we exposed cultures to 50 roM ethanol for 10 days and withdrew them for 1-day. Addition cultures were exposed to 1.0 uM CORT during ethanol treatment and during the 1-day withdrawal period. We observed a significant increase in toxicity in each hippocampal sub-region in cultures treated with 1.0 uM CORT during ethanol exposure and withdrawal, with the CAl region being most sensitive to the cytotoxic effects of CORT and ethanol exposure. MK-B01 exposure during the withdrawal period reduced the cytotoxicity associated with CORT exposure and EWD. 13. SUMMARY OF ACTIVITIES (Do not exceed 3 pages.) A. CHANGES Since submission of the last application/progress report, have any significant changes occurred in the training program, particularly the research project, academic status, or time distribution of activities (Le., percentage of time devoted to research project, course work, teaching, etc.)? If so, explain. B. PROGRESS Describe concisely the research performed and research training obtained during the past year. List all courses and publications. Complete the Gender and Minority Inclusion table(s) (see below), if applicable. C. RESEARCH TRAINING PLANS Describe concisely the research and research training planned for the requested budget period, including any course work. A. CHANGES none B. PROGRESS The primary objective of this proposal is to test the hypothesis that: corticosterone exposure potentiates ethanol withdrawal (EWD)-induced toxicity. The primary aim of this proposal will be achieved by: 1. Determining the effects of corticosterone exposure during ethanol exposure and/or withdrawal from chronic ethanol exposure on toxicity utilizing organotypic hippocampal slice cultures from neonatal rat brain. The aim of this set of experiments was to characterize the effects of corticosterone (CORT) exposure during the withdrawal period from lO-day ethanol exposure. We chose an ethanol treatment regiment that itself does not cause significant cytotoxicity upon withdrawal (i.e. 50 roM) and non-toxic CORT concentrations. When CORT was exposed to cultures at the initiation of ethanol withdrawal, a concentration-dependent effect was observed. In the CA1 region, 0.1 uM CORT increased cytotoxicity above control cultures and cultures withdrawn from 10-day ethanol exposure. In cultures treated with 1.0 uM CORT during the withdrawal period, a significant increase in cytotoxicity was observed above cultures treated with 0.1 uM CORT during EWD. In addition, 1.0 uM CORT exposure during EWD resulted ih significant cytotoxicity in the dentate gyrus, an effect that was not observed at any other CORT concentration or in cultures withdrawn from ethanol. An attenuation of cytotoxicity induced by CORT and EWD was observed in cultures treated with 20 uM MK-801 during the withdrawal period. In the final set of experiments, we exposed cultures to 50 roM ethanol for 10 days and withdrew them for 1-day. Addition cultures were exposed to 1.0 uM CORT during ethanol treatment and during the 1-day withdrawal period. We observed a significant increase in toxicity in each hippocampal sub-region in cultures treated with 1.0 uM CORT during ethanol exposure and withdrawal, with the CA1 region being most sensitive to the cytotoxic effects of CORT and ethanol exposure. MK-801 exposure during the withdrawal period reduced the cytotoxicity associated with CORT exposure and EWD.
StatusFinished
Effective start/end date9/30/039/29/05

Funding

  • National Institute on Alcohol Abuse and Alcoholism: $27,832.00

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