BRAIN BLOOD FLOW IMAGING OF COCAINE WITHDRAWAL & CRAVING

描述：(申请人摘要) 可卡因的流行产生了对药物治疗的需求， 可能会抑制可卡因药物戒断过程中的烦躁不安， 或者是强烈的暗示引发的渴望，这种渴望往往发生在复发之前。可卡因 戒断被归因于中脑边缘多巴胺的枯竭，而 线索诱导的渴望与大脑中多巴胺释放增加有关。 相同的大脑区域。证实特定的大脑区域参与了 无论是退出还是渴望，都将是理解中的重要一步 以及在这些州的治疗中。拟议的研究将衡量和 定位可卡因戒断过程中大脑活动的变化 线索诱导的人类渴望状态，测试关于边缘的假说 在两个州都有牵连。大脑活动的变化将从 局部脑血流量(RCBF)的变化，已知与 大脑突触活动。其他研究将评估该病毒的特异性。 效果，使用rCBF范式。其中一个长期目标是 研究是一种单次会议程序，可同时用于 筛选潜在的“抗戒断”和“抗渴求”属性 治疗可卡因依赖的药物。 具体地说，初步研究将对戒毒者的rCBF模式进行成像 以静息基线为特征的单次治疗中的可卡因患者 条件(研究1a)与可卡因相关和非毒品线索的接触 (研究1b)。一组年龄和性别匹配的对照组，没有可卡因 历史将在同样的条件下被描绘出来。将对rCBF进行成像 使用正电子发射拓扑学(PET)扫描完成 放射性标记(0-15)水作为流动示踪剂。关于撤资问题 (研究1a)，假设是最近戒酒的静息rCBF 可卡因使用者可能比对照组相对较低，特别是在 中脑边缘多巴胺区域被认为对维持欣快感很重要。 这些区域的活动不足可能是一些人感到烦躁不安的原因 可卡因戒断后吸食可卡因的人。关于渴望(研究1b)， 假设可卡因患者边缘区域的rCBF可能 对可卡因线索的反应增加，反映了药物样唤醒和 通常伴随着线索诱导的可卡因渴求的欣快感。试点数据 支持这一假设：几个边缘区域的rCBF增加 在可卡因使用者的可卡因提示期间显著，但这种激活 在没有可卡因病史的受试者中，这种模式并不明显。研究2(线索 特异性)将有助于排除非特定的、未学习的反应 通过测试可卡因与鸦片相关的边缘模式的来源 可卡因患者的(与病史无关的)线索。这项研究还将 构成对研究1a和1b研究结果的潜在重复。 研究3(状态特异性)将排除常见的获得性反应， 焦虑，作为边缘发现的来源，通过测量中央和 对引发焦虑的主观反应与鸦片类药物(与历史无关) 可卡因患者的线索。 对于每个患者，功能性PET图像将与MRI共同配准 (磁共振成像)，产生边缘流动数据并进行比较 地区。单因素方差分析将用于比较患者静息rCBF与 左右半球对照，跨越边缘和非边缘 区域(研究1a)，并将测量线索之间rCBF的变化 边缘和非边缘区域的条件，左侧与右侧 大脑半球，患者(研究2，研究3)和患者与对照组 (研究1b)。关联性将考察主观与主观之间的关系 症状和静息边缘rCBF(研究1a)，以及症状和 可卡因线索(研究1b；研究2)或焦虑线索时激活的rCBF (研究3)。

DESCRIPTION: (Applicant's Abstract) The cocaine epidemic has produced a demand for pharmacologic treatments that may blunt either the dysphoria during pharmacologic withdrawal from cocaine, or the intense cue-triggered craving that often precedes relapse. Cocaine withdrawal has been attributed to mesolimbic dopamine depletion, while cue-induced craving has been linked to increased dopamine release in the same brain regions. Confirming the involvement of specific brain regions in either withdrawal or craving would be an important step in the understanding and in the treatment of these states. The proposed studies will measure and localize the change in brain activity during cocaine withdrawal and cue-induced craving states in humans, testing hypotheses about limbic involvement in both states. Changes in brain activity will be inferred from changes in regional cerebral blood flow (rCBF), known to closely reflect brain synaptic activity. Additional studies will assess the specificity of the effects, using the rCBF paradigm. One long-term objective of these studies is a single-session procedure that could be used simultaneously to screen for "anti-withdrawal" and "anti-craving" properties in potential medications for cocaine dependence. Specifically, the initial studies will image patterns of rCBF in abstinent cocaine patients during a single session featuring a resting baseline condition (Study 1a) and exposure to Cocaine-related and to Non-drug cues (Study 1b). A group of age and sex-matched controls without a cocaine history will be imaged under the same conditions. Imaging of rCBF will be accomplished with PET (Positron Emission Topography) scans, using radioactively labeled (0-15) water as the flow tracer. Regarding withdrawal (Study 1a), the hypothesis is that resting rCBF in recently abstinent cocaine users may be relatively lower than in controls, particularly in mesolimbic dopamine regions considered important for maintaining euthymia. Hypoactivity in these regions may underlie the dysphoria experienced by some cocaine users following cocaine cessation. Regarding craving (Study 1b), the hypothesis is that rCBF in the limbic regions of cocaine patients may increase in response to cocaine cues, reflecting the drug-like arousal and euphoria which often accompany cue-induced cocaine craving. Pilot data support this hypothesis: rCBF in several limbic regions increased significantly during cocaine cues in cocaine users, but this activation pattern was not evident in subjects without a cocaine history. Study 2 (cue specificity) will help rule out non-specific, unlearned responses as a source of the limbic pattern by testing Cocaine-related vs. Opiate (history-irrelevant) cues in cocaine patients. This study will also constitute a potential replication of findings from both Study 1a and 1b. Study 3 (state specificity) will rule out a common learned response, anxiety, as the source of the limbic findings by measuring the central and subjective response to Anxiety-provoking vs. Opiate (history-irrelevant) cues in cocaine patients. For each patient, functional PET images will be co-registered with an MRI (Magnetic Resonance Image), yielding flow data for limbic and comparison regions. ANOVAs will be used to compare resting rCBF for patients vs. controls, for left vs. right hemispheres, across limbic and non-limbic regions (Study 1a), and will measure the change in rCBF between cue conditions for both limbic and non-limbic regions, for left vs. right hemisphere, in patients (Study 2, Study 3) and in patients vs. controls (Study 1b). Correlations will examine the relationship between subjective symptoms and resting limbic rCBF (Study 1a), and between symptoms and activated rCBF during cocaine cues (Study 1b; Study 2) or anxiety cues (Study 3).