PET STUDIES OF BRAIN DOPAMINE IN COCAINE ABUSERS

可卡因成瘾的特征是一种强迫自我的模式 以牺牲生命为代价的行政行为。大脑 多巴胺(DA)系统似乎是强化和上瘾的中心 可卡因的特性。我们实验室的研究提供了第一个 活人脑多巴胺系统异常的证据 可卡因滥用者并记录了DA D2受体的减少 可利用性和在[11C]可卡因结合在基底节。此外， 这些变化与额叶新陈代谢减少有关。 基于这些观察，我们建议研究泛函 从症状的角度来看，这些变化的意义 可卡因滥用者所经历的可能是由于 受DA调节的脑区。我们将使用正电子发射断层扫描 (PET)和双示踪剂([11C]拉克洛必利和18FDG)-兴奋剂-挑战 用于确定额叶新陈代谢降低是否 与突触前DA神经元(PDN)功能下降有关。我们会 评估可卡因滥用者和正常对照组的PDN，我们将评估 多巴胺浓度的变化对额叶代谢的影响。 将通过监测DA释放来评估PDN功能 用哌醋甲酯(MP)挑战，这种药物类似于可卡因， 通过抑制DA转运体来增加突触DA。中的更改 将通过测量间接监测突触DA浓度 响应.MP挑战的[11C]raclopide结合的变化。因为 DA与[11C]raclopide竞争DA D2受体，这一策略将 使我们能够测量MP引起的突触DA的相对变化 挑战。为了评估脑内DA的变化与 区域脑功能，每个受试者还将用18FDG进行研究 测量脑部局部葡萄糖代谢。我们假设： (L)可卡因滥用者PDN功能下降，将表现为 减少继发于哌醋甲酯刺激的突触DA变化。 (2)可卡因滥用者额叶新陈代谢减少的部分原因是 PDN功能减退。因此，当给予哌醋甲酯(以增加 DA活动)可卡因滥用者将表现出额叶新陈代谢增加。 我们实验室最近的初步研究支持这些假设和 提出了实验设计和实验方法。对该计划的评估 可卡因滥用者脑内DA变化的功能意义 帮助识别和连接神经化学和神经解剖学底物 这是可卡因成瘾的根本原因。

Cocaine addiction is characterized by a pattern of compulsive self- administration at the expense of life preserving behaviors. The brain dopamine (DA) system appears to be central to reinforcing and addicting properties of cocaine. Studies in our laboratory have provided the first evidence of abnormalities in the brain DA system in the living human cocaine abuser and have documented decreases in DA D2 receptor availability and in [11C]cocaine binding in the basal ganglia. Moreover, these changes were associated with decreased metabolism in frontal areas. Building on these observations, we propose to investigate the functional significance of these changes from the perspective that the symptoms experienced by the cocaine abuser may be a resultant of dysfunction of brain areas modulated by DA. We will use positron emission tomography (PET) and a dual tracer ([11C]raclopride and 18FDG) -stimulant-challenge experimental design to determine whether decreased frontal metabolism is related to decreased function in presynaptic DA neurons (PDN). We will evaluate PDN in cocaine abusers and in normal controls and we will assess the effects that changes in DA concentration have on frontal metabolism. PDN function will be assessed by monitoring DA release in response to a challenge by methylphenidate (MP), a drug which, similar to cocaine, increases synaptic DA by inhibiting the DA transporter. Changes in synaptic DA concentration will be monitored indirectly by measuring changes in [11C]raclopride binding in response to .MP challenge. Because DA competes with [11C]raclopride for DA D2 receptors, this strategy will enable us to measure relative changes in synaptic DA induced by MP challenge. To assess the relationship between changes in brain DA and regional brain function, each subject will also be studied with 18FDG to measure regional brain glucose metabolism. We hypothesize that: (l) Cocaine abusers have decreased function of PDN which will show as reduced changes in synaptic DA secondary to methylphenidate challenge. (2) Reduced frontal metabolism in the cocaine abusers is in part due to decreased function of PDN. Thus when given methylphenidate (to increase DA activity) cocaine abusers will show an increase in frontal metabolism. Recent pilot studies from our laboratory support these hypotheses and the experimental design and methodology proposed. Evaluation of the functional significance of changes in brain DA in the cocaine abuser may help to identify and link the neurochemical and neuroanatomical substrates which underlie cocaine addiction.