ETHANOL SELF ADMINISTRATION AND CYTOCHROME OXIDASE ACTIVITY

拟议的研究将评估长期饮用乙醇的神经生物学后果。这样的研究将确定大脑中对乙醇敏感的区域，并有可能帮助集中治疗策略，以对抗滥用和慢性酒精中毒的神经系统并发症。众所周知，乙醇对脑功能的影响程度和地形是由长期乙醇暴露而改变的。然而，由于目前方法的空间分辨率和与人体酒精中毒研究相关的各种混淆，人体研究受到限制。因此，需要动物研究来直接将饮酒酒精与特定部位的脑功能变化联系起来。迄今为止，对乙醇对动物大脑影响的成像研究使用了专门设计的方法来识别小时间窗内大脑功能的区域模式。因此，它们在定义急性乙醇摄入或急性乙醇戒断反应时非常有用。然而，这些方法不太适合评估大脑功能的长期变化，这些变化是在几小时到几周的时间内发生的。它不敏感的短期现象，如急性乙醇摄入和退出。此外，最近还设计了定量方法。因此，本课题将首先在本实验室建立细胞色素氧化酶组织化学定量评价方法。这些程序包括使用内部标准和定量密度测定法。接下来，将使用这种方法评估啮齿类动物自我给药乙醇的后果。这项工作将作为对摄入乙醇的长期影响的初步评估。我们特别选择了一种自我管理模式来最密切地模拟人类饮酒。CO法的使用将特别有用，因为它避免了与急性酒精摄入或戒断有关的混淆。有明确的迹象表明，人类和动物的脑功能变化是由长期饮酒引起的；这种方法很可能识别出与酒精饮用相关的长期变化的关键部位。

The proposed study will evaluate the neurobiological consequences of prolonged ethanol drinking. Such studies will identify the regions of the brain that are sensitive to ethanol and potentially help to focus treatment strategies to combat abuse and the neurologic complications of chronic alcoholism. It is known that the magnitude and topography of ethanol's effects on brain function are modified by long-term ethanol exposure. Human studies are limited, however, by the spatial resolution of current methods and the various confounds associated with human research on alcoholism. Animal studies are needed, therefore, to directly link ethanol drinking to changes in brain function within specific sites. To date, imaging studies of ethanol's effects in the brains of animals have used methods that were specifically designed to identify the regional pattern of brain function within a small time window. Accordingly, they have been very useful in defining, the response to acute ethanol intake or acute withdrawal. These methods are, however, less well equipped to evaluate long-term changes in brain function which are modified over a period of hours to weeks. It is not sensitive to short-lived phenomena such as acute ethanol intake and withdrawal. Furthermore, quantitative methods have been recently devised. Therefore, the present proposal will first establish the quantitative method of assessing cytochrome oxidase histochemistry in this laboratory. These procedures involve the use of internal standards and quantitative densitometry. Next, the consequences of ethanol self- administration in rodents will be assessed using this method. This effort will serve as an initial evaluation of the long-term effects of ethanol intake. A self-administration paradigm was specifically chosen to most closely model human alcohol drinking. The use of the CO method will be particularly useful because it avoids confounds associated with acute alcohol intake or withdrawal. There are clear indications that changes in brain function result from chronic alcohol intake in humans and animals; this approach is likely to identify key sites that manifest long-term changes associated with ethanol drinking.