PHARMACOLOGIC TREATMENT OF ETHANOL WITHDRAWAL

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The objective of this research is to identify and establish preclinical efficacy of selected drugs for prevention and treatment of acute and protracted withdrawal syndromes in animal models of ethanol dependence. The drugs to be investigated will be selected from the following pharmacological classes: benzodiazepine mixed agonist/ antagonists; 5- hydroxytryptamine agonists and antagonists, adenosine antagonists, N-methyl-D-aspartate antagonists, and calcium channel antagonists. Test subjects will be adult male and female rats. They will be made ethanol-dependent by administering ethanol either in a nutritionally balanced liquid diet or by administering it through inhalation. Ethanol withdrawal will be measured as signs (overt behaviors) and symptoms (behaviors predictive of subjective effects) occurring upon cessation of the ethanol administration. The drugs of interest will be administered either along with ethanol or during the occurrence of the withdrawal syndrome. Efficacious drugs are expected to alleviate withdrawal without substituting for ethanol itself or causing antagonism of ethanol's pharmacology. The animals will be studied for acute withdrawal after their blood ethanol concentrations decline to negligible levels, and for protracted withdrawal after they recover from the acute phase of withdrawal. During the protracted phase, the usual signs of withdrawal have subsided completely and the major symptoms are reduced greatly. A different set of symptoms will be investigated during this phase. These symptoms are based upon reports from humans but animal models were developed for them later. They include behaviors predictive of anxiety, proconvulsive brain state, craving for alcohol, and a number of deficits in cognitive abilities. These symptoms of protracted withdrawal are important because they provide motivation to consume alcohol to avoid their occurrence, even when patients are deterred from seeking alcohol for pleasure. A small number of drugs will be selected for characterization of their behavioral pharmacology to predict their safety. This research is significant because it responds to one of the RFA goals and promises preclinical data that may be directly relevant to the treatment of alcoholism and prevention continuous alcohol abuse in human subjects. It will also provide data on pharmacological treatment of alcoholism in female subjects.