Extinction of Limbic Activation to "Unseen" Cocaine Cues

描述（由申请方提供）：响应NIDA RFA-DA-08-024药物成瘾的消退和药物治疗：可卡因患者在末次给药后数月甚至数年内对可卡因线索表现出显著的持续性欲望和唤醒。这些“抵抗性”反应可能是由于可卡因患者记录的前额叶皮层（PFC）（调节下游边缘系统所必需的区域）（结构和功能）缺陷。“）地区--以及作为灭绝基础的新的学习。除了这种解剖学上的挑战，接受实验室灭绝的可卡因患者仍然敏锐地意识到，“现实世界”的线索仍然是药物可用性的一个很好的预测因素。这种歧视并不难（尽管存在PFC赤字！），并破坏了实验室灭绝对“现实世界”线索的概括。我们最近开发了一种新的“看不见的”线索范式，可以最大限度地减少“PFC问题”和“意识问题”破坏传统的灭绝努力。这种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，杏仁核，OFC），即使完全在意识之外呈现-即，“看不见的”（PLoS ONE，2008）。此外，重复的，未加强的介绍“看不见的”线索没有激活背PFC，这表明PFC可能不是重要的灭绝外的意识。来自这一新范例的试点数据表明DA调节药物（例如，伐尼克兰）将明显有助于减少边缘系统对可卡因线索的激活，这与我们最近证明纹状体多巴胺（DA）是线索效应的一种脑底物（J. Neuroscience，2006）一致。因此，我们将使用“看不见的”线索范式的一个预防变体和一个组间2x2（“看不见”与“看不见”）x（伐尼克兰与安慰剂）设计，以解决可卡因患者的以下目标（每组n=22）在受控居住环境中停留15天期间：具体目标1）使用“看不见的”可卡因线索在意识之外进行的灭绝是否比使用可见线索的传统灭绝更有效（如通过减少的边缘系统激活来索引的，1小时和1天后（“节省”）和48小时后（“泛化”）的真实可卡因视频？具体目标2）：将伐尼克兰（1 mg b.i.d.）与安慰剂相比，是否有助于其中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已经证明，边缘系统对药物线索的反应在多巴胺转运蛋白（DAT 9 VNTR）的“低效”变体的携带者中要强得多，我们将确定DA传输中遗传变异对可卡因线索反应的贡献，我们的灭绝程序，以及伐尼克兰。拟议的基础研究将具有直接的临床相关性，因为伐尼克兰已经被FDA批准用于人类使用（用于吸烟），并且-如果有效-可以很容易地与廉价的“离磁”消光范例相结合，用于治疗可卡因成瘾。 公共卫生相关性： 伐尼克兰辅助边缘系统对“可见”和“不可见”可卡因线索的反应消退。目前的项目测试大脑对可卡因线索的反应是否会在意识之外发生消退，以及部分激动剂伐尼克兰是否会促进消退。

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.