Medications for Alcohol Withdrawal/Brain Damage

Chronic ethanol ingestion results in neurodegeneration with loss of neurons, glial proliferation anventricular and subarachnoid space. Work from our laboratories has demonstrated that chronic ethanolanimals produces an up-regulation of the excitatory N-methyl-D-aspartate (NMDA) subtype of glutamateWe have recently implicated the NMDA receptor system in induction of excitotoxic damage to various nduring ethanol withdrawal. We will test a series of compounds for their effectiveness in protectingcerebellum and cerebral cortex, grown in culture, against ethanol withdrawal induced excitotoxic damthe effectiveness of a novel NMDA receptor channel blocker, (+)-5- aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine(ADCI), which we have previously shown to be an excellent agent fobehavioral hyperexcitability (tremor, convulsions) during ethanol withdrawal in animals. We will alscycloleucine, and low efficacy partial agonists i.e.,; 1-neuroprotective actions in our cell culturewithdrawal excitotoxicity. Finally, we will test a series of gangliosides, including GM1 and GT1b, shave been touted to protect against glutamate-induced excitotoxicity without compromising the initiarelated events accompanying NMDA receptor stimulation. Our studies will generate an understanding ofcompounds are most effective for preventing ethanol withdrawal excitotoxicity and provide a basis foanimals in Phase II of the SBIR program.