MAMMALIAN ALKALOIDS IN ALCOHOL ABUSE

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Mammalian alkaloids result from condensation of neuronal catecholamines or indolamines with chemically reactive carbonyl compounds such as acetaldehyde, an ethanol metabolite which is elevated during alcohol abuse. The overall objective of this project is to elucidate the neurochemical roles of mammalian biogenic alkaloids in alcoholism. This proposal has three major and interrelated aims. The first is to determine the effects of chronic ethanol exposure on the amounts of certain apparently endogenous TIQs and THBCs in the cerebrospinal fluid (CSF), urine and, if possible, blood of Rhesus monkeys (M. macaca), as well as to determine temporal relationships of these alkaloids to blood ethanol and acetaldehyde levels. The second aim is to more completely elucidate the metabolic disposition in rat tissues and intact rats of these alkaloids when employed in radiolabeled forms. Particular attention will be directed at those metabolites arising from microsomally mediated oxidative and cytosolic conjugation routes. The last aim is to determine if chronic exposure to alkaloids (administered with subcutaneous osmotic minipumps) can evoke brain damage in adult or neonatal rats as indicated by biogenic amine and biogenic acid levels, by histochemistry and by electron microscopy. Emphasis will be on the oxidized alkaloid metabolites which bear structure resemblance to known amine neurotoxins. The hypothesis at the basis of these aims is that CNS alkaloids are formed to a greater extent than normal during alcohol abuse, and that one or more of these alkaloids underlie the neuropathology of chronic alcoholism via conversion or oxidation to reactive electrophilic metabolites which bind covalently to neuronal membranes. Essential to the success of the aims are specific, high sensitivity assay techniques that have been developed; namely, fused silica capillary gas chromatography with mass spectrometric detection and deuterated internal standards, and liquid chromatography with both electrochemical and radioactivity detection.