Drug Context-Induced Instrumental Cocaine Seeking: Influence of Memory Reconsolid

药物环境诱发的工具性可卡因寻求：记忆重建的影响

• 批准号: 8530848
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 2.23万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530848
• 关键词: Amygdaloid structure; Animal Model; Anisomycin; Behavior; Bilateral; Brain region; Chronic; Cocaine; Cocaine Dependence; Cocaine Users; Complex; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Dopamine; Dorsal; Dose; Drug Addiction; Elements; Extinction (Psychology); Fiber; Freezing; Fright; Glutamates; Goals; Hippocampus (Brain); Hyperactive behavior; Maps; Marshal; Measures; Mediating; Memory; Methodology; Modeling; Neurobiology; Neuronal Plasticity; Nucleus Accumbens; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Play; Prevention; Procedures; Protein Biosynthesis; Rattus; Recovery; Relapse; Relative (related person); Research; Retrieval; Role; Self Administration; Self-Administered; Short-Term Memory; Signal Pathway; Signal Transduction; Site; Stimulus; Sum; Testing; Tetrodotoxin; Thinking; Time; Training; Work; addiction; base; calmodulin-dependent protein kinase II; cocaine exposure; cocaine use; cue reactivity; disorder later incidence prevention; drug addiction pharmacotherapy; drug relapse; effective therapy; information processing; inhibitor/antagonist; interest; long term memory; neuroadaptation; neurobiological mechanism; neurochemistry; neurotransmission; novel; protein expression; public health relevance; research study; response; theories

DESCRIPTION (provided by applicant): Successful treatment of cocaine dependence must involve the prevention of environmentally-induced cocaine relapse. Drug-context-induced cocaine relapse relies on the utilization of long-term memories of context- response-cocaine associations. These associative memories can become labile upon retrieval, and must undergo protein synthesis-dependent re-stabilization (i.e., reconsolidation) in order to be maintained in long- term memory. Abnormally enhanced memory reconsolidation may contribute to intrusive thoughts about cocaine and strong cue reactivity, which are the hallmarks of drug addiction. Hence, manipulations that disrupt cocaine memory reconsolidation or inhibit pathological cocaine memories are of tremendous interest from an addiction treatment perspective. Understanding the putative relationship between pathological cocaine memory reconsolidation and drug relapse is a complex problem that requires a two-part approach: (1) identification of the neurobiological substrates of memory reconsolidation that promote drug-context-induced drug seeking and (2) discovery of pathology within these substrates. Focusing on the first objective, the overarching goal of this project is to elucidate essential, and previously uncharacterized, functional neuroanatomical and cellular mechanisms of memory reconsolidation that facilitate drug-context-induced instrumental cocaine seeking. The project will rely upon our previous work, which has demonstrated that protein synthesis in the basolateral amygdala (BLA) and the functional integrity of the dorsal hippocampus (DH) are necessary for cocaine memory reconsolidation and subsequent drug-context-induced cocaine seeking in rats. However, it is unclear whether there is obligatory interaction between these brain regions. Thus, Aim 1 will be to begin to map the putative cocaine memory reconsolidation circuitry. Experiments will test the hypothesis that sequential information processing by the DH and BLA is required for cocaine memory reconsolidation that facilitates subsequent context-induced cocaine seeking. Additional experiments will evaluate whether the nucleus accumbens core and shell, two efferents of the above brain regions, are a part of this circuitry. Based on our previous work, Aim 2 will center on putative cellular mechanisms of cocaine memory reconsolidation in the BLA. It has been postulated that cocaine-induced neuroplasticity, notably enhanced cAMP- and Ca2+ dependent cellular signaling, may trigger pathological memory reconsolidation. To examine two basic assumptions of this idea, experiments will test the hypothesis that (A) the activity of these pathways in the BLA is necessary for cocaine memory reconsolidation and that (B) mimicking the increase in the activity of these signaling pathways putatively produced by chronic cocaine administration is sufficient to potentiate cocaine memory reconsolidation and context-induced cocaine seeking. In sum, this project will explore the neurobiology of cocaine memory reconsolidation to provide a rationale for future research into pathological cocaine memory reconsolidation and for the development of novel pharmacotherapies for drug addiction.

描述（由申请人提供）：可卡因依赖的成功治疗必须包括预防环境诱导的可卡因复吸。药物情境诱发的可卡因复吸依赖于对情境-反应-可卡因关联的长期记忆的利用。这些关联记忆在检索时可能变得不稳定，并且必须经历依赖于蛋白质合成的再稳定化（即，重新巩固）以便在长期记忆中保持。异常增强的记忆再巩固可能有助于对可卡因的侵入性想法和强烈的线索反应，这是药物成瘾的标志。因此，从成瘾治疗的角度来看，破坏可卡因记忆再巩固或抑制病理性可卡因记忆的操纵是非常有趣的。理解病理性可卡因记忆再巩固和药物复发之间的假定关系是一个复杂的问题，需要两部分的方法：（1）识别记忆再巩固的神经生物学底物，促进药物背景诱导的药物寻求和（2）发现这些底物中的病理。专注于第一个目标，这个项目的总体目标是阐明重要的，以前没有特点的，功能性神经解剖和细胞机制的记忆重新巩固，促进药物上下文诱导的工具可卡因寻求。该项目将依赖于我们以前的工作，这表明，蛋白质合成在基底外侧杏仁核（BLA）和背海马（DH）的功能完整性是必要的可卡因记忆再巩固和随后的药物环境诱导的可卡因寻求大鼠。然而，目前还不清楚这些大脑区域之间是否存在强制性的相互作用。因此，目标1将是开始绘制假定的可卡因记忆再巩固回路。实验将检验这样的假设：可卡因记忆重新巩固需要DH和BLA进行顺序信息处理，从而促进随后的上下文诱导的可卡因寻找。另外的实验将评估是否神经核的核心和壳，上述大脑区域的两个传出，是这个电路的一部分。基于我们以前的工作，目标2将集中在BLA中可卡因记忆再巩固的假定细胞机制。据推测，可卡因诱导的神经可塑性，显著增强cAMP和Ca 2+依赖的细胞信号传导，可能引发病理性记忆再巩固。为了检验这一想法的两个基本假设，实验将检验以下假设：（A）BLA中这些通路的活性是可卡因记忆再巩固所必需的，以及（B）模拟慢性可卡因给药所产生的这些信号通路活性的增加足以增强可卡因记忆再巩固和情境诱导的可卡因寻找。总之，本项目将探索可卡因记忆再巩固的神经生物学，为未来研究病理性可卡因记忆再巩固和开发药物成瘾的新药物提供理论基础。