Context-induced Cocaine Relapse: Influence of Cocaine Memory Reconsolidation

项目总结/摘要 由于暴露于可卡因相关的环境背景而引发的顽固的可卡因渴望是一个主要的 导致药物复发的因素。这种现象依赖于对环境的长期记忆- 反应药物协会。最近的研究结果表明，联想记忆在提取时变得不稳定 并且需要经历蛋白质合成依赖的重新整合成长期记忆储存， 随着时间的推移而保留。可卡因诱导的记忆再巩固病理可能导致异常突出或 侵入性可卡因记忆表现为增加的线索反应性和药物复吸的倾向， 相关环境。因此，这项研究计划的长期目标是提高我们对 可卡因记忆再巩固的功能神经解剖学和细胞机制。前一 在资助期间，我们已经表明，蛋白质合成依赖的记忆再巩固发生在 基底外侧杏仁核值得注意的是，这个过程在功能上依赖于背侧的神经活动， 海马，即使这两个大脑区域不共享单突触连接。逻辑延伸 在这项竞争性的更新应用中，具体目标1将确定新的记忆 再合并电路基于我们新的初步发现，我们将检验以下假设： 蓝斑是背侧海马体和基底外侧杏仁核之间的中继， 记忆再巩固此外，我们将评估如何抑制特定的途径，在这个假定的 电路改变每个通路的靶向末端区域的电生理活性。前一 在资助期间，我们还确定了可卡因记忆再巩固所必需的细胞机制。 系统地扩展这一研究路线，具体目标2将确定可卡因的新细胞机制 基底外侧杏仁核的记忆再巩固根据我们的初步研究结果，目标2将侧重于 内源性大麻素（eCB）、花生四烯酸（AEA）和2-花生四烯酸甘油（2-AG）。 我们将评估记忆再巩固足以产生eCB水平变化的程度， 退化和基底外侧杏仁核内的锥体细胞兴奋性。此外，我们将测试 假设AEA抑制-而2-AG促进-不稳定可卡因记忆的重新巩固， 激活基底外侧杏仁核内记忆再巩固的必要细胞介质。到 为了实现这些目标，我们将利用复杂的行为，新颖的光遗传学功能断开， 电生理记录方案，以及免疫组织化学，定量Western印迹， eCB生化测定。总的来说，更新这一富有成效的研究计划有可能显着 推进我们对可卡因记忆再巩固的神经基础的理解，并提供一个必要的 未来研究和成瘾治疗开发工作的概念框架。

PROJECT SUMMARY/ABSTRACT Intractable cocaine craving precipitated by exposure to a cocaine-associated environmental context is a major factor contributing to drug relapse. This phenomenon depends on available long-term memories of context- response-drug associations. Recent findings indicate that associative memories become labile upon retrieval and need to undergo protein synthesis-dependent reconsolidation into long-term memory stores in order to be retained over time. Cocaine-induced pathology in memory reconsolidation may result in unusually salient or intrusive cocaine memories that manifest as increased cue reactivity and propensity for drug relapse in a drug- associated environment. Thus, the long-term goal of this research program is to enhance our understanding of the functional neuroanatomy and cellular mechanisms of cocaine memory reconsolidation. During the previous funding period, we have shown that protein synthesis-dependent memory reconsolidation occurs in the basolateral amygdala. Remarkably, this process is functionally dependent on neural activity in the dorsal hippocampus, even though the two brain regions do not share monosynaptic connections. Logically extending this line of research in this competitive renewal application, Specific Aim 1 will identify novel memory reconsolidation circuits. Based on our new preliminary findings, we will test the hypothesis that the locus coeruleus serves as a relay between the dorsal hippocampus and basolateral amygdala to permit cocaine memory reconsolidation. In addition, we will evaluate how the inhibition of specific pathways within this putative circuitry alters electrophysiological activity at the targeted terminal region of each pathway. During the previous funding period, we also identified cellular mechanisms that are necessary for cocaine memory reconsolidation. Systematically extending this line of research, Specific Aim 2 will identify novel cellular mechanisms of cocaine memory reconsolidation in the basolateral amygdala. Based on our preliminary findings, Aim 2 will focus on the endocannabinoids (eCB), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in the basolateral amygdala. We will evaluate the extent to which memory reconsolidation is sufficient to produce changes in eCB levels, eCB degradation, and pyramidal cell excitability within the basolateral amygdala. In addition, we will test the hypothesis that AEA inhibits - whereas 2-AG facilitates – the reconsolidation of labile cocaine memories and the activation of a requisite cellular mediator of memory reconsolidation within the basolateral amygdala. To accomplish these Aims, we will utilize sophisticated behavioral, novel optogenetic functional disconnection, and electrophysiological recording protocols, as well as immunohistochemistry, quantitative Western blotting, and eCB biochemical assays. Overall, renewal of this productive research program has the potential to significantly advance our understanding of the neural basis of cocaine memory reconsolidation and to provide an essential conceptual framework for future research and addiction treatment development efforts.