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）：成功治疗可卡因依赖性必须涉及预防环境引起的可卡因复发。药物含量诱导的可卡因复发取决于对上下文反应可卡因关联的长期记忆的利用。这些关联记忆在检索后可能会不稳定，并且必须经历蛋白质合成依赖性的重新稳定（即重新固定），以维持在长期记忆中。异常增强的记忆重新整合可能会导致有关可卡因和强烈提示反应性的侵入性思想，这是药物成瘾的标志。因此，从成瘾治疗的角度来看，破坏可卡因记忆重新溶解或抑制可卡因记忆的操纵引起了极大的兴趣。了解可卡因记忆重新溶解与药物复发之间的推定关系是一个复杂的问题，需要采用两部分的方法：（1）鉴定记忆重新溶解的神经生物学底物，以促进药物粘膜诱导的药物寻求药物的寻求和（2）在这些底物中发现病理学。关注这个项目的首要目标是阐明记忆重新溶解的基本和以前没有特色的，功能性的神经解剖和细胞机制，以促进促进药物含量诱导的工具性可卡因寻求。该项目将依靠我们以前的工作，该工作表明基底外侧杏仁核（BLA）中的蛋白质合成，并且背侧海马（DH）的功能完整性对于可卡因记忆重新溶解和随后的药物 - 偏见引起的可可症诱导的可可选择是必需的。但是，尚不清楚这些大脑区域之间是否存在强制性相互作用。因此，目标1将开始映射推定的可卡因记忆重新溶解电路。实验将检验以下假设：可卡因记忆重新溶解需要进行DH和BLA的顺序信息处理，从而促进了随后的上下文引起的可卡因寻求。其他实验将评估伏隔核的核心和外壳（上述大脑区域的两个侵蚀）是否是该电路的一部分。基于我们以前的工作，AIM 2将集中在BLA中可卡因记忆的推定细胞机制上。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，可能会触发病理记忆重新整合。 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.总而言之，该项目将探讨可卡因记忆重新溶解的神经生物学，以为可卡因记忆重新溶解的未来研究和开发用于药物成瘾的新药物治疗提供基本原理。