HUMAN BRAIN FUNCTION AND DRUG ABUSE

该项目旨在识别导致药物依赖的脑功能异常，并为开发新的治疗方式提供线索。我们的策略包括通过正电子发射断层扫描（PET）和[F-18]氟脱氧葡萄糖来评估可卡因滥用者对可卡因的渴望与脑功能之间的关系以及冒险与脑功能之间的关系；使用PET和[O-15]水的风险承担与脑功能之间的关系以及抑制不适当反应的能力与脑功能之间的关系；以及使用[0-15]-水PET测量脑血流量来确定尼古丁对脑功能的认知影响。与药物滥用者比对照组前额叶体积更小的发现相一致，我们发现，多种药物滥用者（n=30）在对人类眶额叶损伤敏感的冒险任务上的表现明显比对照组（n=24）差，但在威斯康星卡片分类任务（一项标准的额皮质神经心理学测试）中却没有。此外，在PET研究中测量了在进行冒险任务时大脑的激活情况，药物滥用者的眶额叶皮层的激活程度低于对照组。这些数据表明，多种药物滥用与前额皮质特定部位的功能缺陷有关。一项用PET和[O-15]-水测量尼古丁对脑功能影响的评估显示，12名戒烟（12小时）尼古丁依赖吸烟者的记忆表现似乎是由不同的神经基质介导的，这表明长期暴露于尼古丁会改变认知策略或为记忆服务的神经系统。在工作记忆任务（N-Back测试）中，尼古丁增加了对照组的区域激活，但在吸烟者中没有，这表明耐受性的发展。

This project aims to identify abnormalities in brain function that contribute to dependence on drugs, and to offer leads in developing new treatment modalities. Our strategies include evaluating the relationship between cocaine craving and brain function and between risk taking and brain function in cocaine abusers as measured by positron emission tomography (PET) and [F-18]fluorodeoxyglucose; the relationship between risk taking and brain function and between the ability to inhibit inappropriate responses and brain function using PET and [O-15]water; and determining cognitive effects of nicotine on brain function using the [0-15]-water PET to measure cerebral blood flow. Consistent with findings of a smaller total volume of the prefrontal lobe in substance abusers compared to controls, we found that polydrug abusers (n=30) performed significantly more poorly than controls (n=24) on a risk taking task that is sensitive to orbitofrontal damage in humans, but not on the Wisconsin Card Sorting Task, a standard neuropsychological test of frontal cortical function. Furthermore, in PET studies measuring brain activation during the performance of the risk taking task, drug abusers show less activation in the orbital frontal cortex than control subjects. These data suggest that polydrug abuse is associated with functional deficits in specific portions of the prefrontal cortex. An evaluation of the effects of nicotine on brain function, as measured by PET with [O-15]-water showed that memory performance in 12 abstinent (12 h) nicotine-dependent smokers seems to be mediated by different neural substrates than those in 12 non-dependent controls, suggesting that chronic exposure to nicotine alters cognitive strategies or neural systems subserving memory. Regional activation during performance of a working memory task (N-Back test) was increased by nicotine in controls, but not in smokers, suggesting the development of tolerance.