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。人类研究是 然而，很难解释，因为他们经常被 不完整和多样的吸毒史、多药滥用和共病 精神变态学。这些问题中的许多可以通过使用 动物。可卡因功能后果的过去研究 在非人类灵长类动物中，给药的重点是立即反应 与急性注射可卡因有关，而长期的变化 功能活动还没有得到充分的描述。细胞色素氧化酶 (CO)是线粒体电子传递链中的一个重要酶 通过氧化磷酸化将燃料转化为ATP。该地区 组织氧化磷酸化的能力被持续的改变 在几小时、几天或一段时间内发生的能源需求水平 几个星期，并已多次被证明与持续的变化有关 神经活动。这种活动可以在大脑中定量地显示出来 组织切片和区域值可以通过定量确定 密度计量学。细胞色素氧化酶活性的组织化学评估是一种 与其他指标相辅相成的长期脑能量代谢指标 代谢图谱技术，如2[14C]脱氧葡萄糖，测量 短期的、由刺激引起的代谢率变化。的总目标是 这项拟议的研究是为了调查吸食可卡因的长期影响。 非人灵长类动物死后组织脑功能的研究 长期自我注射可卡因的人。为此， 一种定量评价细胞色素氧化酶活性的方法 在老鼠身上培育出来的基因将适应非人类灵长类动物。此外， 高、低负荷引起的脑能量代谢模式 将在非人类地区确定自我给药可卡因的剂量 与可卡因效应相关的灵长类大脑：纹状体和两个 在其主要的边缘输入中，杏仁核和眶前叶皮质。这个 拟议研究的结果将使我们更清楚地了解 长期吸食可卡因引起的脑功能全面改变 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.