Neuronal hyperexcitability and epileptiform activity due to withdrawal from chronic ethanol exposure encompasses a continuing problem for the modem clinician. The N-methyl-D-aspartate receptor/channel complex potently regulates the development of epileptiform activity in both in vitro and in vivo neural systems. Ethanol effects upon NMDA systems may be of primary importance for the expression of epileptiform activity especially in relation to the development of, and our ability to treat, alcohol withdrawal seizures. We propose to test the hypothesis that chronic ethanol exposure and subsequent withdrawal modifies the functioning of the NMDA complex resulting in changes in the induction and expression of epileptiform activity. The primary aim of this proposal is to increase our understanding and treatment of epileptiform activity which accompanies chronic ethanol exposure and withdrawal (alcohol withdrawal seizures). This proposal utilizes the electrographic seizure model (EGSs) elicited in the in vitro rat hippocampal slice. A comprehensive analysis of the effects of acute and chronic ethanol exposure and withdrawal on the processes responsible for induction and expression of hippocampal electrographic seizures is proposed. Extracellular recording techniques win be used to identify changes in hippocampal EGSs. Tight seal whole-cell voltage clamp recording techniques (in vitro slice patch) will be used to directly identify and measure cellular changes due to ethanol exposure. Initial evidence shows that ethanol markedly elevates the threshold for the expression of established hippocampal EGSs. This action of ethanol occurs at concentrations known to inhibit NMDA processes. The inhibitory effect of in vitro ethanol exposure is similar to the effect of the NMDA receptor antagonist, D-APV, which also raises the EGS threshold. These data indicate that the NMDA complex may be an important site of ethanol action resulting in modification of seizure generation. Analysis of ethanol effects on seizure processes should increase our understanding and aid in the development of novel therapies for alcohol withdrawal seizures.
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