Context-induced Cocaine Relapse: Influence of Cocaine Memory Reconsolidation

情境诱发的可卡因复吸：可卡因记忆再巩固的影响

• 批准号: 9896796
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 37.8万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896796
• 关键词: 2-arachidonylglycerol; Amygdaloid structure; Anatomy; Behavior; Behavioral; Biochemical; Biological Assay; Brain region; Cells; Cocaine; Cocaine Dependence; Complex; Data; Desire for food; Development; Dorsal; Electrophysiology (science); Endocannabinoids; Environment; Exposure to; Extracellular Signal Regulated Kinases; Frequencies; Funding; Goals; Hippocampus (Brain); Immunohistochemistry; Kinetics; Lead; Learning; Link; Literature; Maps; Mediating; Mediator of activation protein; Memory; Neighborhoods; Neuroanatomy; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Procedures; Process; Protein Biosynthesis; Protocols documentation; Public Health; Pyramidal Cells; Relapse; Research; Research Project Grants; Retrieval; Role; Site; Stimulus; Synapses; Synaptic plasticity; Testing; Time; Update; Western Blotting; addiction; anandamide; base; cannabinoid receptor; cocaine exposure; cocaine relapse; craving; cue reactivity; disorder later incidence prevention; drug craving; drug maintenance; drug relapse; endocannabinoid signaling; endogenous cannabinoid system; fear memory; insight; locus ceruleus structure; long term memory; neural circuit; neuronal excitability; novel; optogenetics; programs; relating to nervous system; response; therapeutic target; therapy development

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.

项目摘要/摘要 通过暴露于可卡因相关的环境环境是一个主要的可卡因渴望精度 导致药物缓解的因素。这种现象取决于上下文的可用长期记忆 - 响应 - 毒品协会。最近的发现表明，回收时的关联记忆变得不稳定 并需要将蛋白质合成依赖性重新溶解为长期记忆存储，以便为 随着时间的流逝。可卡因诱导的记忆重新溶解中可卡因诱导的病理可能会导致异常显着或 侵入性可卡因记忆表现为提示反应性和药物可靠性的可靠性 - 相关环境。这是该研究计划的长期目标是增强我们对 可卡因记忆重新整合的功能性神经解剖学和细胞机制。在上一个 资金期，我们已经表明蛋白质合成依赖性记忆重新溶解发生在 基底外侧杏仁核。值得注意的是，此过程在功能上取决于背侧的神经活动 即使两个大脑区域没有单突触连接，海马。逻辑上扩展 在此竞争性更新应用中的这一研究线，特定的目标1将确定新的记忆力 重新溶解电路。根据我们的新初步发现，我们将检验以下假设。 凝血充当背侧海马和大副杏仁核之间的继电器以允许可卡因 记忆重新整合。此外，我们将评估该推定的特定途径的抑制 电路在每个途径的靶向末端区域改变电生理活性。在上一个 资金期，我们还确定了可卡因记忆重新溶解所必需的细胞机制。 系统地扩展了这一研究，具体目标2将确定可卡因的新细胞机制 重质杏仁核中的记忆重新溶解。根据我们的初步发现，AIM 2将重点放在 内源性大麻素（欧洲央行），anandamide（AEA）和2-芳基烯丙基甘油（2-ag），在层杏仁核中。 我们将评估记忆重新整合足以产生欧洲央行水平的变化的程度，欧洲央行 基体杏仁核内的降解和锥体细胞兴奋性。此外，我们将测试 AEA抑制AEA的假设 - 而2 AG设施 - 不稳定可卡因记忆的重新整合和 基本杏仁核内记忆重新溶解的必要细胞介体的激活。到 完成这些目标，我们将利用复杂的行为，新颖的光学遗传功能断开，并 电生理记录方案以及免疫组织化学，定量蛋白质印迹和 欧洲央行的生化测定。总体而言，该产品研究计划的续订有可能显着 促进我们对可卡因记忆的神经基础的理解，并提供必不可少的 未来研究和成瘾治疗开发工作的概念框架。