PRIMATE COCAINE ABUSE--CYTOCHROME OXIDASE HISTOCHEMISTRY

描述：（申请人摘要） 对活体人脑的研究表明，长期滥用可卡因 改变大脑功能，这种改变可能是永久性的。 人类研究 然而，很难解释，因为它们经常被 不完整和多样的药物史、多种药物滥用和共病 精神病理学 这些问题中有许多可以通过使用 动物 过去对可卡因功能性后果的研究 在非人灵长类动物中的给药集中于立即反应 可卡因的急性管理，而长期的变化， 功能活动没有得到充分描述。 细胞色素氧化酶 (CO)是线粒体电子传递链的必需酶 通过氧化磷酸化将燃料转化为ATP 区域 组织的氧化磷酸化能力被持续的 在数小时、数天或数天内发生的能源需求水平 数周，并已多次被证明与持续的变化， 神经活动 这种活动可以在大脑中定量可视化 组织切片和区域值可以通过定量测定来确定。 密度测定法 细胞色素氧化酶活性的组织化学评估是一种 长期脑能量代谢指标，补充其他 代谢绘图技术，如2[14C]脱氧葡萄糖， 短期内，刺激诱发的代谢率变化。 的总目标 这项研究的目的是调查可卡因摄入的长期影响。 对非人类灵长类动物死后组织的脑功能的影响 长期自我吸食可卡因的人 为此， 一种评价细胞色素氧化酶活性的定量方法， 在大鼠中开发的基因将被适应于非人类灵长类动物。 此外，委员会认为， 大脑能量代谢的模式是由高和低 自我施用可卡因的剂量将在非人类区域确定， 与可卡因的影响有关的灵长类大脑：纹状体和两个 杏仁核和眶额皮层的主要边缘输入。 的 拟议研究的结果将使人们更清楚地了解 长期服用可卡因导致的大脑功能的全面变化 虐待

DESCRIPTION: (Applicant's Abstract) Studies of the living human brain indicate that long-term cocaine abuse alters brain function, and this change may be permanent. Human studies are difficult to interpret, however, because they are often confounded by incomplete and varied drug histories, polydrug abuse, and comorbid psychopathology. Many of these problems can be obviated by the use of animals. Past studies of the functional consequences of cocaine administration in non-human primates have focused on the immediate response to an acute administration of cocaine, whereas long-term changes in functional activity have not been adequately described. Cytochrome oxidase (CO) is an essential enzyme of the mitochondrial electron transport chain that converts fuels into ATP via oxidative phosphorylation. The regional capacity of tissue for oxidative phosphorylation is modified by sustained levels of energy demand that take place over a period of hours, days or weeks and has been repeatedly shown to be linked to persistent changes in neural activity. This activity can be quantitatively visualized in brain tissue sections, and regional values can be determined by quantitative densitometry. Histochemical assessment of cytochrome oxidase activity is an index of long-term cerebral energy metabolism that complements other metabolic mapping techniques such as 2[14C]deoxyglucose that measures short-term, stimulus-evoked changes in metabolic rates. The overall goal of the proposed study is to investigate the long-term effect of cocaine intake on brain function as evaluated in post-mortem tissue from non-human primates that have chronically self-administered cocaine. To that end, the quantitative method of assessing cytochrome oxidase activity that has been developed in the rat will be adapted to non-human primates. Furthermore, the pattern of cerebral energy metabolism resulting from a high and a low dose of self-administered cocaine will be determined in regions of non-human primate brain associated with the effects of cocaine: the striatum and two of its primary limbic inputs, the amygdala and orbitofrontal cortex. The results of the proposed studies will provide a clearer understanding of the comprehensive changes in brain function that result from long-term cocaine abuse.