ROLE OF OPIATES IN ALCOHOL-INDUCED NEUROTOXICITY

已知中枢阿片肽参与神经和 酒精中毒的行为并发症。所涉及的细胞机制 在乙醇中调节的阿片活性目前是难以捉摸的，因为 缺乏可靠的实验模型系统。这项提案的目标是 是为了确定乙醇和下丘脑之间的相互作用 阿片肽β-内啡肽，通过使用一种新开发的方法 在原代培养中维持分离的胎儿下丘脑神经元。 将进行研究以确定：a)急性和非传染性疾病的影响 慢性酒精处理对β-内啡肽分泌的影响， 神经元存活率和形态；b)代谢的影响 乙醇对β-内啡肽分泌、神经元活力和细胞周期的影响 形态；c)对阿片合成的分子调控的影响 在急性和慢性乙醇及其代谢物治疗之后。 多肽将通过放射免疫测定法进行测定，mRNA水平将被 用RNA保护法测定。本研究将：1)建立 β-内啡肽的分泌和合成在多大程度上 培养的神经元受乙醇的影响；2)阐明急性、适应性 和戒断反应，以及3)确定代谢的影响 乙醇对阿片肽的作用。此外，它可能有助于 开发了解乙醇机理的新方法 对阿片肽的作用，并可能指示有效的治疗方法 酒精引起的神经毒性。

Central opioid peptides are known to be involved in the neurological and behavioral complications of alcoholism. The cellular mechanism involved in ethanol-regulated opioid activity is elusive at present because of a lack of reliable experimental model systems. The goal of this proposal is to determine the interaction between ethanol and the hypothalamic opioid peptide Beta-endorphin, by using a newly developed method for maintaining isolated fetal hypothalamic neurons in primary cultures. Studies will be conducted to determine: a) the effect of acute and chronic treatments of ethanol on the secretion of Beta-endorphin, neuronal viability and morphology; b) the metabolic influences of ethanol action on Beta-endorphin secretion, neuronal viability and morphology; c) the effect on molecular regulation of opioid synthesis following acute and chronic ethanol and its metabolite treatments. Peptides will be measured by radioimmunoassay, and mRNA levels will be determined by RNA protection assay. This study will: 1) establish to what extent the secretion and synthesis of Beta-endorphin-containing neurons in culture is affected by ethanol; 2) elucidate acute, adaptive and withdrawal responses, and 3) identify the metabolic influences of ethanol action on the opioid peptide. Furthermore, it may help in developing novel approaches to understanding the mechanisms of ethanol action on opioid peptides, and may indicate effective therapies for ethanol-induced neurotoxicity.