DISULFIRAM METABOLISM--ALCOHOLISM TREATMENT CONCEPTS

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The disulfiram-ethanol-reaction (DER) will be studied in rats in order to correlate the pharmacokinetic aspects of disulfiram and its metabolites diethyldithiocarbamate and diethyldithiocarbamate-methyl ester with the pharmacodynamics of the DER. Biochemical parameters to be measured include plasma disulfiram, diethyldithiocarbamate, diethyldithiocarbamate-methyl ester, CS2 and diethylamine. Blood ethanol and acetaldehyde as well as brain and liver aldehyde dehydrogenase (low and high Km) in mitochondrial, lysomal, microsomal and supernatant fractions will be determined. Physiological measurements will include heart rate, blood pressure, and core temperature. Using drugs as pharmacological tools, the role of aldehyde dehydrogenase, dopamine-Beta-hydroxylase, acetaldehyde, and ethanol in the DER will be evaluated. Ascorbate-protein binding interactions in vivo in rats, its effect on negating the DER, and the correlation with the various biochemical and physiological parameters will be studied. The pharmacodynamics of the DER also will be investigated to delineate the role of brain dopamine and norepinephrine receptors. Included are studies employing the central administration of 6-hydroxydopamine, a catecholamine neurotoxin, to study the interaction between disulfiram and ethanol in producing the DER.