Human Brain Function And Drug Abuse

该项目的总体目标是确定导致或导致药物依赖的大脑功能模式，并为开发新的治疗方法提供线索。我们的研究策略包括使用正电子发射断层扫描（PET）来评估各种药物滥用和认知激活对大脑活动的影响，使用[F-18]氟脱氧葡萄糖的葡萄糖代谢率和使用[O-15]-水的局部脑血流量，受体占用[C-11]雷氯必利和磁共振成像（MRI）来评估药物滥用的结构后遗症。 为了了解药物渴求的病理生理学，阐明药物渴求的神经机制是必要的。虽然以前的研究已经将多巴胺与渴望的各个方面联系起来，但没有直接证据表明多巴胺在药物渴望行为中释放。使用[C-11]雷氯必利和PET，我们测量细胞外多巴胺活性。受试者在观看和收听中性线索时进行扫描，然后在可卡因线索呈现期间进行第二次扫描。多巴胺活性用雷氯必利结合电位的百分比变化表示，我们用雷氯必利结合电位作为多巴胺释放的量度。多巴胺的释放在报告有渴望的参与者的右前壳核中明显大于那些没有报告的参与者。此外，渴求的强度与左后壳核的多巴胺释放呈正相关。这些结果提供了第一个直接的证据表明，在人类背侧纹状体细胞外多巴胺的释放增加与主观可卡因渴望的增加成比例。 美沙酮维持治疗是阿片类药物成瘾的主要治疗方法，但围绕其在长期治疗中使用的优点存在争议。15名无美沙酮（6-24个月）阿片类药物滥用者，12名接受美沙酮维持（稳定剂量超过6个月）的阿片类药物滥用者和13名对照受试者参加了本研究。美沙酮戒断受试者在双侧膝周和左侧扣带回中部的相对代谢活性较低，通过[F-18]氟脱氧葡萄糖和PET测量。与此相反，美沙酮维持组受试者在左侧丘脑、丘脑和左侧顶下小叶表现出较低的相对活性（与对照组相比）;然而，他们在膝周前扣带回和右侧顶下小叶中的活性高于对照组。在美沙酮戒断受试者中，抑郁的测量与左膝周回和中扣带回的相对活动呈正相关;在对照受试者中，类似的关联呈负相关。美沙酮维持的受试者表现出负协方差之间的状态措施的抑郁症和相对活动的右下顶叶小叶和右膝周前扣带回，抑郁症和相对活动的左下顶叶小叶之间的特质措施。美沙酮维持治疗可改善负性情感状态下神经回路的功能异常，但可抑制阿片受体密度高的某些区域的脑功能。 我们证明了重度大麻使用者在爱荷华州决策任务中表现出缺陷，但与非使用者相比，在Stroop冲突任务中没有表现出缺陷。使用基于体素的形态测量法，发现重度大麻使用者的样本在结构MR图像上的前叶区域和中央前回的脑组织组成（灰质和白色物质）与非使用者相比发生了改变。

The overall goal of this project is to identify patterns of brain function that contribute to or result from dependence on drugs, and to suggest leads in the development of new treatment methods. Our research strategies involve the use of positron emission tomography (PET) to evaluate the effect of various drugs of abuse and cognitive activation on brain activity using cerebral metabolic rates for glucose using [F-18]fluorodeoxyglucose and regional cerebral blood flow using [O-15]-water, receptor occupancy [C-11]raclopride and and magnetic resonance imaging (MRI) to evaluate structural sequelae of drug abuse. To understand the pathophysiology of drug craving, it is essential to elucidate the neural substrates of drug craving. Although previous studies have linked dopamine to aspects of craving, there is no direct evidence that dopamine is released during drug craving behavior. Using [C-11]raclopride and PET, we measured extracellular dopamine activity. Subjects were scanned while watching and listening to neutral cues, followed by a second scan during presentations of cocaine cues. Dopamine activity was expressed using the percentage change in raclopride binding potential, which we used as a measure of dopamine release. Dopamine release was significantly greater in the right anterior putamen of participants who reported craving than in those who did not. Further, the intensity of craving was positively correlated with dopamine release in the left posterior putamen. These results provide the first direct evidence that extracellular dopamine release in human dorsal striatum increases proportionately with subjective increases in cocaine craving. Methadone maintenance is the primary treatment for opiate addiction, but controversy surrounds the merits of its use in long-term treatment. Fifteen methadone-free (6-24 months) opiate abusers, twelve opiate abusers receiving methadone maintenance (stable dose over 6 months), and thirteen control subjects participated in this study. Methadone-withdrawn subjects had lower relative metabolic activity measured by [F-18]fluorodeoxyglucose and PET than control subjects in bilateral perigenual and the left middle cingulate gyrus. In contrast, methadone-maintained subjects exhibited lower relative activity (vs. control) in the left insula, the thalamus, and the left inferior parietal lobule; however, they exceeedded control aactivity in the perigenual anterior cingulate gyrus and the right inferior parrietal lobule. Measures of depression covaried positively with relative activity in the left perigenual and mid-cingulate gyrus in methadone-withdrawn subjects; analogous associations in control subjects covaried negatively. Methadone-maintained subjects exhibited negative covariance between state measures of depression and relative activity in the right inferior parietal lobule and the right perigenual anterior cingulate, and between trait measures of depression and relative activity in the left inferior parietal lobule. Methadone maintenance ameliorates functional abnormalities in the neural circuitry sub-serving negative affective states, but depresses brain function in some regions of high opiate receptor density. We demonstrated that heavy marijuana users have performance deficits on the Iowa decision-making task, but not on the Stroop conflict task when compared to non-users. A sample of heavy marijuana users was found to have altered brain tissue composition (gray matter and white matter) in the hippocampa region and precentral gyrus on structural MR images compared to non-users using voxel-based morphometry.