MAMMALIAN ALKALOIDS IN ALCOHOL ABUSE

哺乳动物生物碱是由神经元儿茶酚胺或 吲哚胺类化合物具有化学反应活性的化合物，如 乙醛，一种酒精代谢物，在酒精中会升高 虐待。这个项目的总体目标是阐明 哺乳动物生物碱在酒精中毒中的神经化学作用。这 提案有三个主要且相互关联的目标。第一个是确定 慢性酒精暴露对大鼠脑内某些物质含量的影响 脑脊液中明显的内源性TIQ和THBCs， 如有可能，还包括恒河猴(M.Macaca)的尿液和血液，以及 确定这些生物碱与血液中乙醇和 乙醛水平。第二个目标是更全面地阐明 这些生物碱在大鼠组织和正常大鼠体内的代谢 当以放射性标记的形式使用时。我们将特别注意 在这些代谢产物中产生的微粒子介导的氧化和 胞质接合途径。最后一个目标是确定慢性 暴露于生物碱(皮下注射渗透性微泵) 可以引起成年或新生大鼠的脑损伤，这是生物起源的 组织化学和电子方法测定的胺和生物酸水平 显微镜。重点将放在氧化的生物碱代谢物上， 熊的结构与已知的胺类神经毒素相似。假设是在 这些目的的基础是中枢生物碱形成了更大的 在酗酒期间比正常程度更大，并且其中一个或多个 生物碱是慢性酒精中毒转化的神经病理基础 或氧化为活性亲电代谢物，与之共价结合 神经细胞膜。目标成功的关键是具体， 已经开发的高灵敏度分析技术；即融合 硅胶毛细管气相色谱-质谱联用检测 氚内标物和高效液相色谱柱 电化学和放射性检测。

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.