Context-induced Cocaine Relapse: Influence of Cocaine Memory Reconsolidation

项目摘要/摘要 暴露在与可卡因相关的环境中导致的顽固性可卡因渴求是一个主要的 导致毒品复发的因素。这种现象依赖于对语境的长期记忆-- 应对--药物协会。最近的发现表明，联想记忆在提取时变得不稳定 需要经历依赖蛋白质合成的重新整合到长期记忆存储中，才能 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显著的或 侵入性可卡因记忆，表现为药物中线索反应性和药物复发倾向的增加- 关联环境。因此，这项研究计划的长期目标是增进我们对 可卡因记忆再巩固的功能神经解剖学和细胞机制。在上一次 资助期，我们已经表明，依赖蛋白质合成的记忆重新巩固发生在 杏仁基底外侧核。值得注意的是，这个过程在功能上依赖于背部的神经活动。 海马体，尽管这两个大脑区域并不共享单突触连接。在逻辑上延伸 这一行的研究将在这一竞争性的更新应用中，明确目标1将识别新的存储器 重新整合电路。根据我们新的初步发现，我们将检验这个假设 蓝斑是背侧海马体和杏仁基底外侧核之间的中继器，允许可卡因进入大脑。 记忆重新巩固。此外，我们还将评估特定通路的抑制如何在这个推定的 电路改变了每条通路目标末端区域的电生理活动。在上一次 在资助期间，我们还确定了可卡因记忆重新巩固所必需的细胞机制。 系统地扩展这一研究路线，《特定目标2》将确定可卡因的新细胞机制。 杏仁基底外侧核的记忆再巩固。根据我们的初步发现，目标2将专注于 杏仁基底外侧核内的内源性大麻素(ECB)、花生胺(AEA)和2-花生四烯酸甘油(2-AG)。 我们将评估记忆重新整合在多大程度上足以导致ECB水平的变化，ECB 基底外侧杏仁核内锥体细胞的兴奋性。此外，我们还将测试 假设AEA抑制不稳定的可卡因记忆的重新巩固，而2-AG促进 杏仁基底外侧核内记忆重新巩固所必需的细胞介体的激活。至 为了实现这些目标，我们将利用复杂的行为、新颖的光遗传功能断开，以及 电生理记录方案，以及免疫组织化学、定量Western blotting和 欧洲央行生化检测。总体而言，更新这一富有成效的研究计划有可能显著 加深我们对可卡因记忆再巩固的神经基础的理解，并提供必要的 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.