Mechanisms Regulating Cocaine Memory Strength

调节可卡因记忆强度的机制

• 批准号: 9919523
• 负责人: Mary M Torregrossa
• 金额: $ 34.65万
• 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: 2016-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919523
• 关键词: Address; Amygdaloid structure; Behavior; Behavioral; Behavioral Mechanisms; Calcineurin; Calmodulin; Chemosensitization; Clinical; Cocaine; Cues; Data; Electrophysiology (science); Equilibrium; Event; Extinction (Psychology); Female; Goals; Homosynaptic Depression; Individual; Learning; Maintenance; Measures; Mediating; Memory; Methods; Modeling; Molecular; Neuronal Plasticity; Pathway interactions; Pattern; Pharmaceutical Preparations; Phosphopeptides; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphoserine; Phosphotransferases; Physiological; Process; Protein Analysis; Protein Dephosphorylation; Proteomics; Rattus; Regulation; Relapse; Reporting; Research; Research Personnel; Role; Self Administration; Serine; Sex Differences; Signal Pathway; Signal Transduction; Societies; Synapses; Testing; Time; Tissues; Training; Viral; addiction; base; calcineurin phosphatase; calmodulin-dependent protein kinase II; cohort; conditioned fear; craving; cue reactivity; disorder later incidence prevention; drug of abuse; effective therapy; experimental study; fear memory; follow-up; improved; male; memory process; mimetics; mutant; non-drug; novel; phosphoproteomics; pre-clinical; prevent; therapy development

Project Summary/Abstract Addictive disorders are a huge burden on both the individual and on society. Unfortunately, there are few effective treatments, partially due to the persistence of drug-associated memories that drive craving and relapse. Therefore, recent research has focused on finding ways to reduce the strength of drug-associated memories to prevent relapse. Memory strength can be reduced by either disrupting the association between a cue and a drug via extinction or by inhibiting the reconsolidation of the memory after a reminder event. Both strategies have been effective in preclinical and clinical models, but in some cases, a memory meant to be weakened, is instead strengthened due to unintentional enhancement of reconsolidation or inhibition of extinction. In order to address this problem, we have analyzed changes in protein phosphorylation after a memory undergoes extinction vs. reconsolidation to identify signaling cascades that are selective to either memory process, or that ideally regulate the two processes in opposite directions. Identification of opposing signaling events could allow the development of treatments that both enhance extinction and inhibit reconsolidation, reducing the strength of the drug-associated memories that drive relapse. Our preliminary data strongly suggest that opposing Ca2+-related signaling events in the basolateral amygdala (BLA) mediate the reconsolidation vs. extinction of a memory associated with self-administered cocaine. We will expand our identification of opposing signaling events in Aim 1 of the proposed studies, including increasing the number of proteins analyzed, expansion of the time course of analysis, and extending the analysis to females. Moreover, we will follow-up on the exciting findings from our initial study, which include 1) identification of a novel phosphorylation event on Ca2+ -calmodulin-dependent kinase 2 alpha (CaMKIIα, phospho-serine 331) induced by extinction and reduced during reconsolidation that functions to inhibit kinase activity, and 2) a general decrease in protein phosphorylation after extinction, implicating activation of a phosphatase, such as calcineurin. Our data led us to hypothesize that extinction training, in addition to involving new learning mechanisms, can also oppose normal reconsolidation processes. We propose that this occurs within the same circuits via Ca2+-regulated synaptic depotentiation mechanisms. Extinction-induced synaptic depotentiation and differences in CaMKII and calcineurin signaling have been reported for conditioned fear memories, but have not been examined for cocaine-associated memories. Thus, using a combination of approaches in Aims 2 & 3, we will determine if CaMKIIα inhibition via S331 phosphorylation, and activation of calcineurin phosphatase, can reduce cocaine memory strength to decrease cue-induced reinstatement via enhancement of extinction AND inhibition of reconsolidation. We will also determine if these signaling pathways directly regulate each other and synaptic strength in the same or different pathways. Determination of the mechanisms regulating cocaine memories will lead to novel targets for relapse prevention treatment development.

项目概要/摘要 成瘾性疾病对个人和社会都是巨大的负担。不幸的是，很少有 有效的治疗，部分原因是与药物相关的记忆的持续存在，这些记忆会驱动渴望和 复发。因此，最近的研究重点是寻找降低药物相关强度的方法。 记忆以防止复发。破坏记忆力之间的关联可以降低记忆强度。 提示和药物通过消退或在提醒事件后抑制记忆的重新巩固。两个都 策略在临床前和临床模型中是有效的，但在某些情况下，记忆意味着 由于无意中增强了再巩固或抑制了 灭绝。为了解决这个问题，我们分析了蛋白质磷酸化后的变化。 记忆经历消退与重新巩固，以识别对任一记忆有选择性的信号级联 记忆过程，或者理想地以相反的方向调节这两个过程。反对者的识别 信号事件可以允许开发既增强灭绝又抑制 重新巩固，降低导致复发的药物相关记忆的强度。我们的初步数据 强烈建议基底外侧杏仁核 (BLA) 中相反的 Ca2+ 相关信号传导事件介导 与自我注射可卡因相关的记忆的重新巩固与消失。我们将扩大我们的 拟议研究的目标 1 中识别相反的信号事件，包括增加 分析蛋白质，延长分析时间，并将分析范围扩大到女性。而且， 我们将跟进我们最初研究的令人兴奋的发现，其中包括 1) 识别一部小说 Ca2+ -钙调蛋白依赖性激酶 2 α（CaMKIIα，磷酸丝氨酸 331）诱导的磷酸化事件 通过消退并在再巩固过程中减少，起到抑制激酶活性的作用，2）一般 灭绝后蛋白质磷酸化减少，表明磷酸酶被激活，例如 钙调磷酸酶。我们的数据使我们假设，除了涉及新的学习之外，灭绝训练 机制，也可能反对正常的再巩固过程。我们建议这发生在同一时间 通过 Ca2+ 调节的突触去电位机制的电路。灭绝诱导的突触去潜能 据报道，CaMKII 和钙调磷酸酶信号传导的差异与条件性恐惧记忆有关，但是 尚未检查与可卡因相关的记忆。因此，在目标中使用多种方法的组合 2 和 3，我们将确定 CaMKIIα 是否通过 S331 磷酸化和钙调神经磷酸酶激活来抑制 磷酸酶，可以降低可卡因记忆强度，从而通过增强减少提示诱导的恢复 消退和再巩固的抑制。我们还将确定这些信号通路是否直接 在相同或不同的途径中相互调节和突触强度。机制的确定 调节可卡因记忆将导致预防复发治疗开发的新目标。