PET STUDIES OF BRAIN DOPAMINE IN COCAINE ABUSERS

描述：(申请人摘要) 虽然多巴胺(DA)似乎对可卡因的增强至关重要，但它的 参与可卡因的失控和强制使用 可卡因成瘾者的情况就不那么清楚了。使用我们已经展示的PET 纹状体DA D2受体持续减少，主要是 位于可卡因滥用者体内的GABA细胞上。这一发现与GABA的 作为DA的效应者的角色使我们假设GABA系统 参与可卡因成瘾。我们假设慢性可卡因 给药导致GABA功能失调，进而 影响GABA对多巴胺的调节以及大脑对多巴胺的反应 刺激。在这项拨款中，我们建议评估GABA能系统在 戒毒和戒毒期间的可卡因滥用者，以及 用一种增强GABA的药物治疗。 我们将通过监测大脑区域来间接评估GABA系统 代谢反应(用2-脱氧-2[18F]氟-D-葡萄糖和PET测量) 劳拉西潘，一种苯二氮卓类药物，可增强GABA活性。我们会 劳拉西潘与安慰剂治疗可卡因滥用者的疗效比较 30例，测试1~2周，最后一次吸食可卡因后6~8周复测。 正常对照组(n=20)将进行平行测试(1-3岁)。在4-5年内 我们将评估使用γ-乙烯基氨基丁酸进行6周治疗的效果 GABA能增强药(GVG)对大鼠大脑对劳拉西潘反应的影响 可卡因滥用者(n=30)。我们的工作假设是：(1)可卡因滥用者 会对继发性GABA能刺激有更高的敏感性 对GABA功能降低的适应。这将显示为增强的 对劳拉西潘的脑代谢反应将具有地区性和 在戒毒后还会留下来。(2)使用GVG治疗将有助于 规范GABA能失调，恢复二次适应 流程。因此，GVG治疗将降低增强的区域 可卡因滥用者对劳拉西潘的代谢敏感性。研究项目： 我们实验室的实验动物和可卡因滥用者的试验工作 支持这些假设。此外，因为在实验动物中，GABA 增强药物可减弱可卡因的增强作用和衰减作用 可卡因引起的多巴胺增加，这些研究的发现是 相关性不仅仅是从理解神经化学的角度 成瘾的底物，也用于开发新的治疗方法 可卡因滥用。

DESCRIPTION: (Applicant's Abstract) While dopamine (DA) appears to be crucial for cocaine reinforcement, its involvement in the loss of control and compulsive administration of cocaine in the cocaine addict is much less clear. Using PET we have shown persistent reductions in striatal DA D2 receptors, which are predominantly located on GABA cells, in cocaine abusers. This finding coupled to GABA's role as an effector for DA led us to postulate that the GABA system participates in cocaine addiction. We hypothesize that chronic cocaine administration leads to disregulation of GABA function, which in turn affects GABA modulation of DA as well as cerebral response to DA stimulation. In this grant we propose to evaluate the GABAergic system in cocaine abusers during withdrawal and detoxification, and the effects of treatment with a GABA enhancing drug. We will assess the GABA system indirectly by monitoring the regional brain metabolic response (measured with 2-deoxy-2[18F]fluoro-D-glucose and PET) to lorazepam, a benzodiazepine drug which enhances GABA activity. We will compare the effects of lorazepam to those of placebo in cocaine abusers (n=30) tested 1-2 weeks and then retested 6-8 weeks after last cocaine use. Normal controls (n=20) will be tested in parallel (years 1-3). In years 4-5 we will evaluate the effects of a 6 week treatment with gamma-vinyl GABA (GVG), a GABAergic enhancing drug, on the brain's response to lorazepam in cocaine abusers (n=30). Our working hypotheses are: (1) Cocaine abusers will have an increased sensitivity to GABAergic stimulation secondary to adaptations from decreased GABA function. This will appear as an enhanced brain metabolic response to lorazepam which will be regionally specific and will remain after detoxification. (2) Treatment with GVG will serve to normalize the GABAergic disregulation and restore the secondary adaptation processes. Hence GVG treatment will decrease the enhanced regional metabolic sensitivity to lorazepam in cocaine abusers. Studies in laboratory animals and pilot work from our laboratory in cocaine abusers support these hypotheses. Furthermore, because in laboratory animals GABA enhancing drugs decrease the reinforcing effects of cocaine and attenuate cocaine-induced increases in DA, findings from these studies are of relevance not only from the perspective of understanding neurochemical substrates of addiction, but also for the development of new treatments for cocaine abuse.