The Role of Amygdalar CaMKII in Cocaine-Associated Memory Extinction and Reconsolidation

杏仁核 CaMKII 在可卡因相关记忆消退和再巩固中的作用

• 批准号: 9045201
• 负责人: Matthew T Rich
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045201
• 关键词: Abstinence; Amino Acids; Amygdaloid structure; Attenuated; Behavior; Biochemical; Brain; Calcium; Calcium Channel; Calcium/calmodulin-dependent protein kinase; Caliber; Chronic; Clinical; Cocaine; Confocal Microscopy; Cues; Data; Dendritic Spines; Development; Drug usage; Extinction (Psychology); Fluorescent Dyes; Future; Glutamates; Head; Image Analysis; Individual; Lead; Learning; Long-Term Potentiation; Maintenance; Measures; Memory; Modeling; Morphology; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phosphorylation; Phosphotransferases; Prevention therapy; Problem Solving; Process; Protein Biosynthesis; Protein Kinase; Proteins; Rattus; Relapse; Resolution; Retrieval; Role; Self-Administered; Signal Transduction; Signaling Molecule; Slice; Stimulus; Structural Genes; Synapses; Testing; Therapeutic; Time; Tissues; Training; Vertebral column; Western Blotting; Work; addiction; base; calmodulin-dependent protein kinase II; craving; density; design; disorder later incidence prevention; drug of abuse; drug relapse; drug seeking behavior; improved; inhibitor/antagonist; learning extinction; memory consolidation; memory recall; neurobiological mechanism; novel; postsynaptic; prevent; public health relevance; receptor; relapse risk; research study; synaptic function; therapy design; trafficking; transmission process; treatment strategy; voltage

 DESCRIPTION (provided by applicant): Successful treatment of addictive disorders depends not only on obtaining, but also on maintaining abstinence, and therefore preventing relapse is an essential therapeutic approach. Relapse is often triggered by environmental cues that signal availability of the drug, inducing the retrieval of drug-associated memories. Disrupting cue-induced memories is a new strategy for reducing relapse risk and can be accomplished via one of two approaches: (1) by preventing reconsolidation of a reactivated memory or (2) by extinction of the memory. When a memory is retrieved it enters a labile state and protein synthesis-dependent restabilization (reconsolidation) is necessary for the long-term maintenance of the memory. To prevent reconsolidation, drug- related cues are briefly presented followed by an intervention designed to inhibit the re-storage of the memory, thus reducing the ability of the memory to invoke craving and relapse in the future. Alternatively, when drug- associated cues are repeatedly presented in the absence of the drug, the individual learns that the cues are no longer predictive of drug availability, leading to less craving, and a subsequent inhibition of drug-seeking behavior. This learning process is called memory extinction. Although extinction and reconsolidation involve some of the same neurobiological processes, there may be components of the two pathways that diverge, allowing the development of a single medication that simultaneously enhances extinction and inhibits reconsolidation. A major limitation in previously tested medications has been the unintentional strengthening of the drug-associated memory by reconsolidation rather than extinction enhancement. However, a treatment strategy that concurrently alters extinction and reconsolidation would solve this problem. Drugs of abuse alter excitatory signaling within the basolateral amygdala (BLA) and other memory centers of the brain, leading to biochemical and structural synaptic changes that result in pathologically strengthened memories. This proposal will use a rat model of addiction to study the mechanistic and functional role of calcium/calmodulin dependent protein kinase II alpha (CaMKIIa), a protein activated by the influx of calcium through N-methyl-D-aspartate (NMDA) receptors, following cocaine-associated memory extinction and reconsolidation and to validate it as a target for relapse prevention. CaMKIIa activation leads to its autophosphorylation and translocation to dendritic spines, as well as phosphorylation of synaptic targets including glutamatergic receptors and related structural proteins. CaMKII has been implicated in a number of memory paradigms, but its specific role following drug- associated memory extinction and reconsolidation has been poorly studied. The proposed studies will test the hypothesis that differential activation of CaMKII in th BLA following cocaine-associated memory manipulations alters the phosphorylation patterns of synaptic proteins, subsequently impacting dendritic spine morphology and cocaine-seeking behavior. The proposal will evaluate the potential of a manipulation of CaMKII or a downstream signaling molecule as a potential pharmacological treatment for the prevention of relapse.

 描述（由申请人提供）：成瘾性疾病的成功治疗不仅取决于获得，而且取决于保持戒断，因此预防复发是一种重要的治疗方法。复发通常是由环境线索触发的，这些环境线索表明药物的可用性，诱导药物相关记忆的检索。破坏线索诱导的记忆是降低复发风险的一种新策略，可以通过两种方法之一来实现：（1）通过防止重新激活的记忆的重新巩固或（2）通过记忆的消失。当记忆恢复时，它进入不稳定状态，蛋白质合成依赖的再稳定（再巩固）对于记忆的长期维持是必要的。为了防止再巩固，药物相关的线索被简要地呈现，然后是被设计为抑制记忆的再储存的干预，从而降低记忆在未来引起渴望和复发的能力。或者，当在没有药物的情况下重复呈现药物相关的线索时，个体了解到这些线索不再预测药物的可用性，从而导致更少的渴望和随后的药物寻求行为的抑制。这种学习过程被称为记忆消退。虽然消退和再巩固涉及一些相同的神经生物学过程，但这两种途径可能存在分歧，从而允许开发一种同时增强消退和抑制再巩固的单一药物。以前测试过的药物的一个主要限制是通过重新巩固而不是消除增强无意中加强了药物相关的记忆。然而，同时改变消退和再巩固的治疗策略将解决这个问题。滥用药物会改变基底外侧杏仁核（BLA）和大脑其他记忆中心内的兴奋性信号，导致生物化学和结构性突触变化，从而导致病理性记忆增强。该提案将使用成瘾大鼠模型来研究钙/钙调蛋白依赖性蛋白激酶II α（CaMKIIa）的机制和功能作用，CaMKIIa是一种通过N-甲基-D-天冬氨酸（NMDA）受体的钙内流激活的蛋白质，在可卡因相关记忆消退和再巩固后，并验证其作为复发预防的靶点。CaMKIIa激活导致其自身磷酸化和易位至树突棘，以及包括突触能受体和相关结构蛋白的突触靶的磷酸化。CaMKII与许多记忆范例有关，但其在药物相关记忆消退和再巩固后的具体作用研究甚少。拟议的研究将测试可卡因相关记忆操纵后BLA中CaMKII的差异激活改变突触蛋白的磷酸化模式，随后影响树突棘形态和可卡因寻求行为的假设。该提案将评估操纵CaMKII或下游信号分子作为预防复发的潜在药理学治疗的潜力。