ETHANOL SELF ADMINISTRATION AND CYTOCHROME OXIDASE ACTIVITY

这项拟议的研究将评估长期饮酒的神经生物学后果。这类研究将确定大脑中对乙醇敏感的区域，并可能有助于集中治疗策略，以打击滥用和慢性酒精中毒的神经并发症。众所周知，长期接触酒精会改变酒精对大脑功能的影响程度和影响范围。然而，人类研究受到当前方法的空间分辨率以及与人类对酒精中毒的研究相关的各种混淆的限制。因此，需要进行动物研究，以直接将饮酒与特定部位大脑功能的变化联系起来。到目前为止，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，以确定小时间窗口内大脑功能的区域模式。因此，它们在定义对急性酒精摄入或急性戒断的反应方面非常有用。然而，这些方法不太适合评估大脑功能的长期变化，这些变化需要几个小时到几周的时间才能修改。它对急性酒精摄取和戒断等短暂现象不敏感。此外，最近还设计出了定量方法。因此，本提案将首先在本实验室建立细胞色素氧化酶组织化学的定量评价方法。这些程序涉及使用内部标准和定量密度测定法。下一步，将使用这种方法评估啮齿动物体内乙醇自我给药的后果。这项工作将作为对乙醇摄入的长期影响的初步评估。特别选择了一个自我管理的范例来对人类饮酒进行最接近的模拟。CO方法的使用将特别有用，因为它避免了与急性酒精摄入或戒酒相关的混淆。有明确的迹象表明，人类和动物长期饮酒会导致大脑功能的变化；这种方法可能会确定与饮酒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.