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引起的可卡因复吸。药物环境引起的可卡因复吸依赖于环境反应可卡因关联的长期记忆的利用。这些联想记忆在检索时可能会变得不稳定，并且必须经历蛋白质合成依赖性的重新稳定（即重新巩固）才能维持在长期记忆中。异常增强的记忆重新巩固可能会导致对可卡因的侵入性想法和强烈的提示反应，这是吸毒成瘾的标志。因此，从成瘾治疗的角度来看，破坏可卡因记忆重新巩固或抑制病理性可卡因记忆的操作具有极大的意义。了解病理性可卡因记忆再巩固与药物复发之间的假定关系是一个复杂的问题，需要采用两部分方法：（1）识别记忆再巩固的神经生物学基质，促进药物环境诱导的药物寻求；（2）发现这些基质内的病理学。围绕第一个目标，该项目的总体目标是阐明记忆重建的基本的、以前未表征的功能性神经解剖学和细胞机制，以促进药物环境诱导的工具性可卡因寻找。该项目将依赖于我们之前的工作，该工作已证明基底外侧杏仁核（BLA）中的蛋白质合成和背侧海马（DH）的功能完整性对于可卡因记忆重新巩固和随后的药物环境诱导的大鼠可卡因寻找是必要的。然而，目前尚不清楚这些大脑区域之间是否存在必然的相互作用。因此，目标 1 将是开始绘制假定的可卡因记忆再巩固电路。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，从而促进随后的情境诱导的可卡因寻找。其他实验将评估伏隔核核心和外壳（上述大脑区域的两个传出神经）是否是该电路的一部分。基于我们之前的工作，目标 2 将集中于 BLA 中可卡因记忆重新巩固的假定细胞机制。据推测，可卡因诱导的神经可塑性，特别是增强的 cAMP 和 Ca2+ 依赖性细胞信号传导，可能会触发病理性记忆重新巩固。为了检验这个想法的两个基本假设，实验将检验以下假设：(A) BLA 中这些通路的活性对于可卡因记忆重新巩固是必要的，(B) 模拟长期服用可卡因所产生的这些信号通路活性的增加足以增强可卡因记忆重新巩固和情境诱导的可卡因寻求。总之，该项目将探索可卡因记忆再巩固的神经生物学，为未来病理性可卡因记忆再巩固的研究和开发新的药物成瘾药物疗法提供理论依据。