Alcohol abuse and alcoholism are significant problems in society, and ethanol (EtOH) withdrawal represents one of many serious consequences of chronic drinking. Given the fact that many individuals experience multiple EtOH withdrawal, and that repeated detoxifications have been shown to progressively intensity in severity, it is clear that treatment strategies need to be evaluated for their ability to effectively and (and safely) address this sensitization of """"""""kindling"""""""" of EtOH withdrawal syndromes. Our models of EtOH withdrawals is really suited to address this clinically relevant research issues since evaluations of pharmacologic treatments in preventing or blocking behavioral indices of sensitized withdrawal hyperexcitability may also be extended to evaluation of their effects against electrophysiological and molecular correlates of this withdrawal sensitization phenomenon. A series of anticonvulsant drugs that influence activity at GABAa and NMDA receptor systems (important neural substrates of EtOH withdrawal) will be evaluated for their ability to block or attenuate the development and/or expression of 1) behavioral indices of sensitized withdrawal-related CNS or attenuate the development and/or expression of 1) behavioral indices of sensitized withdrawal-related CNS hyperexcitability, 2) sensitization of electrographic measures of withdrawal-related CNS hyperexcitability and 3) molecular alterations (mRNA and protein expression) of GABAA and NMDA receptor subunits associated with repeated ethanol intoxication and withdrawal. Taken together, the proposed work will employ an established model of multiple EtOH withdrawals and a multi-disciplinary approach in evaluating the efficacy of pharmacologic agents in treating behavioral, electrophysiological and molecular indices of withdrawal sensitization. Results from these studies will provide clinically-relevant information about pharmacotherapy strategies for treating EtOH withdrawal and importantly, the potentially long-term deleterious consequences related to multiple EtOH withdrawal.
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