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， 可能会减弱可卡因药物戒断期间的烦躁不安， 或者是在复发前由强烈的暗示引发的渴望。 可卡因 戒断归因于中脑边缘多巴胺耗竭，而 线索诱导的渴望与大脑中多巴胺释放的增加有关。 相同的大脑区域。 证实了特定的大脑区域参与了 无论是戒断还是渴望都是理解 以及对这些国家的治疗。 拟议的研究将衡量和 定位可卡因戒断期间大脑活动的变化 提示诱导的人类渴望状态，测试关于边缘系统的假设 参与这两个国家。 大脑活动的变化将从 局部脑血流量（rCBF）的变化，已知密切反映 大脑突触活动 其他研究将评估以下方面的特异性 的影响，使用rCBF范式。 其中一个长期目标是 研究是一个单一的会议程序，可以同时使用， 筛选潜在的“抗戒断”和“抗渴望”特性 治疗可卡因依赖的药物 具体来说，最初的研究将图像模式的rCBF在禁欲 可卡因患者在一个单一的会议期间， 条件（研究1a）和暴露于可卡因相关和非药物线索 （研究1b）。 一组年龄和性别匹配的对照组， 历史将在同样的条件下成像。 rCBF成像将 使用PET（正电子发射断层扫描）扫描， 放射性标记的（0-15）水作为流动示踪剂。 关于撤销 （研究1a），假设最近戒断的静息rCBF 可卡因使用者可能相对低于对照组，特别是在 中脑边缘多巴胺区被认为对维持正常情绪很重要。 这些区域的活动减退可能是一些人经历的烦躁不安的基础。 可卡因戒断后的可卡因使用者。 关于渴望（研究1b）， 假设可卡因患者边缘区的rCBF可能 对可卡因线索的反应增加，反映了药物样的觉醒， 通常伴随着线索诱导的可卡因渴望的欣快感。 导频数据 支持这一假设：几个边缘区的rCBF增加 在可卡因使用者的可卡因线索中显着，但这种激活 在没有可卡因史的受试者中模式不明显。 研究2（提示 特异性）将有助于排除非特异性的，未学习的反应， 通过测试可卡因相关与阿片类药物的边缘系统模式的来源 （历史无关）线索在可卡因患者。 本研究还将 构成研究1a和1b结果的潜在复制。 研究3（状态特异性）将排除常见的习得反应， 焦虑，作为边缘系统的研究结果的来源，通过测量中央和 对致幻药与阿片类药物的主观反应（病史无关） 可卡因患者的线索 对于每例患者，功能性PET图像将与MRI共配准 （磁共振成像），产生用于边缘系统和比较的血流数据 地区 将使用ANOVA比较患者与 对照，左半球与右半球，跨边缘系统和非边缘系统 区域（研究1a），并将测量提示之间的rCBF变化 边缘和非边缘区域的条件，左与右 半球，患者（研究2、研究3）和患者与对照 （研究1b）。 相关性将检查主观之间的关系 症状和静息边缘系统rCBF（研究1a），以及症状和 在可卡因线索（研究1b;研究2）或焦虑线索期间激活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).