Mechanisms underlying ethanol withdrawal-induced neurotoxicity and means to reverse this damage are not completely understood. Research suggests that glucocorticoids and polyamines may contribute to ethanol-associated neurodegeneration. Thus, the broad, long-term objective of this proposal is to establish more precisely the mechanisms involving glucocorticoid-induced exacerbation of ethanol withdrawal (EWD)-mediated damage using organotypic hippocampal slice cultures. To this end, cultures will be exposed chronically to ethanol and withdrawn in the presence of corticosterone. Toxicity will then be assessed using the non-vital fluorescent dye propidium iodide. Some studies suggest that EWDinduced damage may be partially mediated via activation of the polyamine-sensitive portion of NMDA receptors. In addition, corticosterone administration may also influence expression of this polyaminesensitive subunit. These hypotheses will be tested using autoradiographic imaging of spermidine's potentiation of [125l]MK-801 binding. The secondary yet therapeutically relevant objective is to examine the efficacy of novel NMDA polyamine-site and glucocorticoid receptor antagonists against corticosterone's potentiation of EWD-induced toxicity. Regardless of the outcomes of the proposed studies, they may provide considerable insight into some of the mechanisms of EWD-mediated hippocampal degeneration, as well as identify potential therapeutic targets for the treatment of alcohol-associated neurodegeneration.
| Butler, T R; Self, R L; Smith, K J et al. (2010) Selective vulnerability of hippocampal cornu ammonis 1 pyramidal cells to excitotoxic insult is associated with the expression of polyamine-sensitive N-methyl-D-asparate-type glutamate receptors. Neuroscience 165:525-34 |
| Mulholland, Patrick J; Self, Rachel L; Hensley, Allison K et al. (2006) A 24 h corticosterone exposure exacerbates excitotoxic insult in rat hippocampal slice cultures independently of glucocorticoid receptor activation or protein synthesis. Brain Res 1082:165-72 |
| Mulholland, P J; Self, R L; Stepanyan, T D et al. (2005) Thiamine deficiency in the pathogenesis of chronic ethanol-associated cerebellar damage in vitro. Neuroscience 135:1129-39 |
| Mulholland, Patrick J; Self, Rachel L; Harris, Barton R et al. (2005) Corticosterone increases damage and cytosolic calcium accumulation associated with ethanol withdrawal in rat hippocampal slice cultures. Alcohol Clin Exp Res 29:871-81 |
