Extinction of Limbic Activation to "Unseen" Cocaine Cues

描述(申请人提供)：针对NIDA RFA-DA-08-024戒毒和药物成瘾药物疗法：可卡因患者在最后一次服药后数月甚至数年对可卡因线索表现出显著的持续欲望和唤起。这些“抗消退”反应可能是由于可卡因患者前额叶皮质(PFC)的(结构性和功能性)缺陷所致--这是调节下游边缘(“GO！”)所必需的区域。区域--以及作为灭绝基础的新知识。除了解剖学上的挑战，正在接受实验室戒毒的可卡因患者仍然敏锐地意识到，“现实世界”的线索仍然是预测药物可获得性的极佳指标。这种歧视并不困难(尽管PFC有赤字！)，并破坏了对实验室灭绝的“真实世界”暗示的概括。我们最近开发了一种新的“看不见的”线索范式，它可能会将破坏传统灭绝努力的“PFC问题”和“意识问题”最小化。这一范式最近提供了第一个证据，表明可卡因线索(33毫秒，向后掩蔽)可以触发皮质下边缘奖赏回路(杏仁核、纹状体/苍白球、脑岛、OFC)，即使在完全在意识之外呈现时也是如此--即“看不见”(PLoS One，2008)。此外，重复、无强化地呈现“看不见的”线索并没有激活背侧的PFC，这表明PFC对于外界意识的灭绝可能不那么重要。来自这一新范式的试点数据表明，DA调节药物(例如，varenicline)将明显有助于减少对可卡因线索的边缘激活，这与我们最近证明纹状体多巴胺(DA)作为线索效应的一种大脑底物是一致的(J.NeuroScience，2006)。因此，我们将使用“看不见”线索范式的消退变体和组间2x2(“看得见”与“看不见”)x(varenicline与安慰剂)设计，以解决在受控居住环境中停留15天期间可卡因患者(每组22人)的以下目标：具体目标1)使用“看不见”可卡因线索在外界意识中进行的消退是否比使用可见线索的传统消退更有效(根据相同线索的边缘激活减少为索引)，1小时和1天后(“节约”)和48小时后的现实可卡因视频(“概括”)？具体目标2)：Will varenicline(1 mg，b.i.d)与安慰剂相比，促进一种或两种消退方法？探索性目的：最后，由于我们的实验室最近证明了携带低效的多巴胺转运体(DAT 9VNTR)变异体的人对药物线索的边缘反应要强得多，我们将确定DA传递中的基因变异对可卡因线索的反应、对我们的灭绝过程以及对varenicline的贡献。拟议的基础研究将具有直接的临床意义，因为varenicline已经被FDA批准用于人类(吸烟)，如果有效的话，可以很容易地与治疗可卡因成瘾的廉价的“无磁”消退范例相结合。 与公共卫生相关：在varenicline的帮助下，对“看得见的”和“看不见的”可卡因线索的边缘反应消失。目前的项目测试对可卡因线索的大脑反应是否可以在意识之外消失，以及部分激动剂varenicline是否可以促进消失。

Description (provided by applicant): In response to NIDA RFA-DA-08-024 Extinction and pharmacotherapies for drug addiction: Cocaine patients show a remarkable persistence of desire and arousal to cocaine cues, months or even years after the last dose of drug. These "extinction-resistant" responses may be due to cocaine patients' documented (structural and functional) deficits in the prefrontal cortex (PFC) - a region necessary for modulating the downstream limbic ("GO!") regions - and for the new learning that underlies extinction. Adding to this anatomical challenge, cocaine patients undergoing laboratory-based extinction remain keenly aware that "real-world" cues are still an excellent predictor of drug availability. This discrimination is not difficult (despite a PFC deficit!), and undermines generalization of laboratory extinction to "real-world" cues. We have recently developed a novel "unseen" cue paradigm that may minimize both "the PFC problem" and " the awareness problem" undermining conventional extinction efforts. This paradigm recently provided the first evidence that cocaine cues (33 msec, backward-masked) can trigger the subcortical limbic reward circuitry (amygdala, striatum/pallidum, insula, OFC) even when presented entirely outside awareness- i.e., "unseen" (PLoS ONE, 2008). Further, repeated, unreinforced presentations of the "unseen" cues did not activate the dorsal PFC, suggesting the PFC may not be as important for extinction outside awareness. Pilot data from this new paradigm suggests DA-modulating medications (e.g., varenicline) will be a clear assist in reducing the limbic activation to cocaine cues, consistent with our recent demonstration of striatal dopamine (DA) as one brain substrate for cue effects (J. Neuroscience, 2006). We will thus use an extinction-variant of the "unseen" cue paradigm and a between-group 2 x 2 ("seen" vs. "unseen") x ( varenicline vs. placebo ) design to address the following aims in cocaine patients (n=22 per group) during a 15-day stay in a controlled residential setting: Specific Aim 1) Will extinction conducted outside awareness, using "unseen" cocaine cues, be more effective than conventional extinction with visible cues (as indexed by reduced limbic activation to the same cues, 1 hour and 1 day later ("savings") and to realistic cocaine videos 48 hours later ("generalization")? Specific Aim 2): Will varenicline (1 mg b.i.d.) facilitate either or both extinction approaches, as compared to placebo? Exploratory Aim: Finally, as our lab has recently demonstrated that the limbic response to drug cues is much stronger in carriers of the "inefficient" variant of the dopamine transporter (DAT 9 VNTR), we will determine the contribution of genetic variations in DA transmission for the response to cocaine cues, to our extinction procedures, and to varenicline. The proposed basic research will have immediate clinical relevance, as varenicline is already FDA- approved for human use (for cigarette smoking) and - if effective -- could readily be combined with inexpensive "off-magnet" extinction paradigms for the treatment of cocaine addiction. PUBLIC HEALTH RELEVANCE: Varenicline-assisted extinction of the limbic response to "seen" and "unseen" cocaine cues. The current project tests whether extinction of the brain response to cocaine cues can occur outside awareness, and whether extinction can be facilitated by the partial agonist varenicline.