Extinction of Limbic Activation to "Unseen" Cocaine Cues

描述（由申请人提供）：根据NIDA RFA-DA-08-024药物成瘾的消退和药物治疗：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欲望和唤醒的持久性。这些“抗灭绝”反应可能是由于可卡因患者在前额叶皮层（PFC）中记录的（结构和功能）缺陷——这是调节下游边缘（“GO!”）所必需的区域。区域——以及灭绝背后的新知识。再加上这个解剖学上的挑战，可卡因患者在实验室中经历的灭绝仍然敏锐地意识到，“现实世界”的线索仍然是药物可用性的一个很好的预测指标。这种区分并不困难（尽管存在PFC缺陷！），并且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。这一模式最近提供了第一个证据，证明可卡因提示（33毫秒，后掩）可以触发皮层下边缘奖励回路（杏仁核，纹状体/白脑，脑岛，OFC），即使完全在意识之外呈现-即“看不见”（PLoS ONE, 2008）。此外，重复的、未经强化的“看不见的”线索的呈现并没有激活PFC的背侧，这表明PFC可能对外部意识的消失没有那么重要。这个新范例的初步数据表明，调节多巴胺的药物（例如，伐尼克兰）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）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”线索范式的灭绝变体和2组之间的2 x 2(“看到的”vs。“看不见的”x （varenicline vs. placebo）设计，旨在解决在受控居住环境中15天内可卡因患者（每组n=22）的以下目标：具体目标1)使用“看不见的”可卡因线索在意识之外进行的消退是否比使用可见线索进行的传统消退更有效（通过减少边缘激活对相同线索，1小时和1天（“节省”）和48小时后的真实可卡因视频（“推广”））？特定目标2)：与安慰剂相比，伐尼克兰（每日1mg）是否会促进其中一种或两种消退方法？探索目的：最后，由于我们的实验室最近证明，多巴胺转运体“低效”变体（DAT 9 VNTR）的携带者对药物提示的边缘反应要强得多，我们将确定DA传递中遗传变异对可卡因提示、我们的灭绝程序和伐尼克兰反应的贡献。拟议的基础研究将具有直接的临床意义，因为varenicline已经被FDA批准用于人类使用（用于吸烟），如果有效，可以很容易地与廉价的“非磁性”消除范例结合起来治疗可卡因成瘾。

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.