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

药物环境诱导的工具性可卡因寻求：记忆重建的影响

• 批准号: 8228172
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 32.05万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228172
• 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. PUBLIC HEALTH RELEVANCE: This project will explore the functional neuroanatomical and cellular mechanisms of memory reconsolidation, which are postulated to stabilize cocaine-related associative memories and facilitate the ability of a drug- predictive context to trigger instrumental cocaine-seeking behavior in a rat model of drug relapse. The project is intended to provide rationale for (A) future research into pathological cocaine memory reconsolidation and (B) for the development of novel and more effective pharmacotherapies for cocaine addiction.

描述（由申请人提供）：可卡因依赖的成功治疗必须包括防止环境诱导的可卡因复发。药物情境诱导的可卡因复发依赖于情境-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变得不稳定，并且必须经过蛋白质合成依赖的再稳定（即再巩固）才能维持在长期记忆中。异常增强的记忆再巩固可能导致对可卡因的侵入性想法和强烈的线索反应，这些都是吸毒成瘾的标志。因此，从成瘾治疗的角度来看，破坏可卡因记忆再巩固或抑制病理可卡因记忆的操作是非常有趣的。理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，需要两部分的方法：(1)识别记忆再巩固的神经生物学基础，促进药物情境诱导的药物寻求；(2)发现这些基础中的病理。着眼于第一个目标，本项目的总体目标是阐明促进药物情境诱导的工具性可卡因寻求的记忆再巩固的基本和以前未被描述的功能性神经解剖学和细胞机制。该项目将依赖于我们之前的工作，该工作已经证明，大鼠的基底外侧杏仁核（BLA）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的重新巩固和随后的药物情境诱导的可卡因寻找是必要的。然而，目前还不清楚这些大脑区域之间是否有强制性的相互作用。因此，目标1将开始绘制假定的可卡因记忆再巩固电路。实验将验证这样的假设：可卡因记忆的再巩固需要DH和BLA的顺序信息处理，从而促进后续情境诱导的可卡因寻求。另外的实验将评估上述大脑区域的两个传出信号——伏隔核核和壳核——是否属于这一回路的一部分。基于我们之前的工作，Aim 2将集中于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，特别是cAMP-和Ca2+依赖性细胞信号的增强，可能引发病理性记忆再巩固。为了检验这一观点的两个基本假设，实验将验证以下假设：(A)脑左脑区这些通路的活性对于可卡因记忆的再巩固是必要的；(B)模仿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的再巩固和情境诱导的可卡因寻求。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新的药物治疗药物成瘾提供理论依据。