Mechanisms Regulating Cocaine Memory Strength

摘要 吸毒是一种严重的疾病，影响着数百万人，给社会造成了巨大的负担。 许多人试图戒烟，但至少有60%的人在一年内复发。因此，故态复萌 预防仍然是成瘾治疗研究的重要目标。复发的主要原因之一是 暴露在环境线索(人、地方和事物)中，提醒个人吸毒和启动 渴望。一种潜在的治疗策略是降低这些药物线索记忆的强度，以便它们 更不能导致新的药物使用。在临床上，这可以使用暴露疗法来实现，这是 基于灭绝学习，并涉及药物相关线索的多个呈现，直到渴望 响应度降低。不幸的是，这种方法只是略微有效。因此，我们调查了 维持和消除可卡因记忆的神经生物学机制，以便 确定潜在的策略，以提高线索暴露疗法的能力，减少复发。我们确认了 神经回路和分子机制都是可卡因记忆形成和消退的基础。 具体地说，我们发现杏仁外侧核(LA)中接受输入的突触的可塑性 可卡因自身给药后丘脑内侧膝状核(MGN)增强， 这种可塑性可以通过线索消退训练来逆转。我们进一步发现，我们可以诱导长期的 MGN-LA突触抑制(LTD)以模仿线索的方式减少复发样行为 灭绝训练。此外，我们还发现，调节这一过程中的激酶和磷酸酶的活性 区域既可以促进消亡学习，也可以破坏记忆重新巩固，以减少复发 MGN-LA突触的强度。因此，在这份支持NIDA夏季研究的行政副刊中 实习生，我们的目标是训练学生如何进行调查可卡因规则的实验- 相关的记忆。实习生将接受培训，进行静脉注射药物自我给药实验，包括 有机会进行外科手术。实习生将接受适当的护理和培训 对啮齿动物的处理以及在物质使用障碍领域使用的常见行为方法。这个 实习生将被指派一个特定的实验来研究GABAB受体作为潜在靶点的作用 可卡因记忆操控。实习生将测试GABAB受体激动剂是否可以作为有用的辅助药物 接受暴露疗法。我们将确定GABAB激动剂是否增强灭绝，防止再巩固，以及是否 药物辅助暴露疗法与线索相关神经活动的变化有关 跨环境。我们将测试GABAB激动剂在直接注入LA时是否有效，以及它们是否有效 当系统地给药时有效。总的来说，拟议的研究旨在提供丰富的培训 对物质使用研究感兴趣的本科生的经验。

Abstract Drug addiction is a serious disorder that affects millions of people and produces a large burden on society. Many individuals try to abstain from use, but at least 60% of people relapse within one year. Thus, relapse prevention remains an important goal for addiction treatment research. One of the primary causes of relapse is exposure to the environmental cues (people, places, and things) that remind individuals of drug use and initiate craving. One potential treatment strategy is to reduce the strength of these drug-cue memories so that they are less able to cause renewed drug use. Clinically, this can be accomplished using exposure therapy, which is based on extinction learning and involves multiple presentations of drug-associated cues until the craving response is reduced. Unfortunately, this approach is only mildly effective. Thus, we have investigated the neurobiological mechanisms underlying the maintenance and extinction of cocaine memories, in order to identify potential strategies for improving the ability of cue exposure therapy to reduce relapse. We identified both neural circuit and molecular mechanisms that underlie cocaine memory formation and extinction. Specifically, we found that plasticity at synapses in the lateral amygdala (LA) that receive inputs from the medial geniculate nucleus of the thalamus (MGN) are strengthened after cocaine self-administration and that this plasticity is reversed by cue extinction training. We further found that we could induce long-term depression (LTD) at MGN-LA synapses to reduce relapse-like behavior in a manner that mimicked cue extinction training. Additionally, we found that modulating the activity of kinases and phosphatases in this region could either promote extinction learning or disrupt memory reconsolidation to reduce relapse and the strength of MGN-LA synapses. Thus, in this administrative supplement to support a NIDA Summer Research Intern, we aim to train the student in how to perform experiments investigating the regulation of cocaine- associated memories. The intern will be trained to perform IV drug self-administration experiments, including being given the opportunity to perform surgical procedures. The intern will be trained in proper care and handling of rodents and in the common behavioral methods used in the substance use disorder field. The intern will be assigned a specific experiment to investigate the role of GABAB receptors as a potential target for cocaine memory manipulation. The intern will test whether GABAB receptor agonists could be useful adjuncts to exposure therapy. We will determine if GABAB agonists enhance extinction, prevent reconsolidation, and if pharmacologically assisted exposure therapy is associated with changes in cue-associated neural activity across contexts. We will test if GABAB agonists are effective when infused directly into the LA, and if they are effective when given systemically. Overall, the proposed studies are designed to provide a rich training experience for an undergraduate fellow interested in substance use research.