PET STUDIES IN COCAINE ABUSE

过去十年美国可卡因滥用的不断升级 以及随之而来的社会、经济和医疗问题， 强烈的兴趣，阐明神经化学机制负责 因为它的愉悦和强化特性。 虽然在动物身上的研究 暗示了可卡因与突触前视神经多巴胺的相互作用 再吸收系统在其增强性能中起主要作用， 在文献中有许多关于 可卡因在多大程度上改变了突触后 多巴胺受体 本申请描述了使用正电子 发射断层扫描（PET）直接映射和表征可卡因结合 用碳11标记的可卡因， 检查（直接在可卡因滥用者中）慢性可卡因的影响 突触前多巴胺再摄取系统的使用和戒断（使用 [11 C]可卡因）和突触后多巴胺D2受体系统， [18F]-N-甲基螺哌啶）。 为了更好地了解神经化学物质 系统参与可卡因的结合，药理学概况 将在狒狒的不同脑区测定可卡因的结合 通过使用标记的可卡因并选择性地阻断多巴胺， 去甲肾上腺素和5-羟色胺再摄取位点进行高度特异性药物治疗。 结合的立体选择性可通过以下的比较PET研究来检查： [11 C]-（-）-可卡因和[11 C]-（+）-可卡因，活性和非活性 药物的对映体。 可卡因滥用对 标记可卡因的结合和[18F]-N- 甲基螺哌利多（测量多巴胺D2受体的可用性）将被 可卡因滥用者中的评估和可卡因诱导的 将测量突触前和突触后多巴胺能系统的变化 三个月的戒毒期 系列PET研究中， 受试者（人或狒狒）作为其自身对照将用于减少 与受试者间差异相关的问题。 具体假设 [11 C]可卡因将与多巴胺再摄取结合， （2）长期使用可卡因会导致多巴胺D2减少 受体和（3）慢性可卡因使用将导致增加 多巴胺再摄取位点伴随可卡因结合增加 的数量，并且随着药物的停用， 结合位点将恢复正常。 直接检查这些 多巴胺能系统在活的大脑和可能性， 与可卡因戒断相关的临床特征 用PET测量的神经化学变化不仅有希望 了解可卡因的神经化学反应， 可卡因成瘾的有效治疗措施。

The escalating abuse of cocaine in the United States over the past decade and its attendant social, economic and medical problems has stimulated intense interest in elucidating the neurochemical mechanisms responsible for its euphoric and reinforcing properties. Although studies in animals have implicated cocaine's interactions with the presynaptic ptic dopamine reuptake system as playing a major role in its reinforcing properties, there are a number of inconsistencies in the literature regarding the extent to which cocaine modifies the activity of post-synaptic dopaminergic receptors. This application describes studies with positron emission tomography (PET) to directly map and characterize cocaine binding sites in living human and baboon brain with carbon-11 labeled cocaine and to examine (directly in cocaine abusers) the effects of chronic cocaine use and withdrawal on presynaptic dopamine reuptake system (using [11C]cocaine) and the post-synaptic dopamine D2 receptor system using [18F]-N- methylspiroperidol). To better understand the neurochemical systems involved in cocaine binding, the pharmacological profile of cocaine binding in different brain regions will be determined in baboons by using labeled cocaine and selectively blocking the dopamine, norepinephrine and serotonin reuptake sites with highly specific drugs. Stereoselectivity of bindinl be examined by comparative PET studies of [11C]-(-)- cocaine and [11C]-(+)-cocaine, the active and inactive enantiomers of the drug respectively. The effects of cocaine abuse on both the binding of labeled cocaine and on the binding of [18F]-N- methylspiroperidol (to measure dopamine D2 receptor availability) will be assessed in cocaine abusers and the reversibility of cocaine induced changes in pre and post-synaptic dopaminergic systems will be measured over a three month drug-free period. Serial PET studies in which the subject (human or baboon) serves as his own control will be used to reduce problems associated with inter-subject variability. Specific hypotheses to be tested are (1) that [11C]cocaine will bind to the dopamine reuptake site, (2) that chronic cocaine use will lead to a decrease in dopamine D2 receptors and (3) that chronic cocaine use will lead to an increase in dopamine reuptake sites accompanied by an increase in cocaine binding sites and that with discontinuation of the drug the number of cocaine binding sites will return to normal. The direct examination of these dopaminergic systems in the living brain and the possibility of correlating clinical characteristics accompanying cocaine withdrawal with neurochemical changes as measured with PET holds the promise not only of understanding the neurochemical response to cocaine but of designing more effective therapeutic measures for cocaine addiction.