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.

项目摘要/摘要 令人上瘾的疾病对个人和社会都是巨大的燃烧。不幸的是，很少 有效的治疗，部分是由于吸引渴望和的毒品相关记忆的持续存在 复发。因此，最近的研究集中于寻找降低药物相关强度的方法 回忆以防止继电器。可以通过破坏一个之间的关联来降低记忆力 提醒事件后，通过延伸或抑制记忆的重新整合来提示和药物。两个都 策略在临床前和临床模型中都是有效的，但是在某些情况下，记忆本来是 由于无意增强或抑制的无意增强，因此被削弱了，而是加强 扩大。为了解决这个问题，我们分析了蛋白质磷酸化的变化 内存进行扩展与重新溶解，以识别选择性的信号级联 内存过程，或理想地以相反的方向调节这两个过程。对立的识别 信号事件可以允许发展既增强延伸又抑制的处理 重新溶解，降低了与药物相关的记忆的强度。我们的初步数据 强烈建议在基体杏仁核（BLA）中相反的Ca2+相关信号事件介导 与自我管理可卡因相关的记忆的重新溶解与扩展。我们将扩大我们的 在拟议的研究的目标1中识别相反的信号事件，包括增加数量 分析的蛋白质，分析时间过程的扩展，并将分析扩展到女性。而且， 我们将跟进我们最初研究中令人兴奋的发现，其中包括1）识别新颖的发现 Ca2+ -calmodulin依赖性激酶2α（CaMKIIα，磷酸丝氨酸331）上的磷酸化事件诱导 通过延伸并减少重新溶解的功能抑制激酶活性，2）一般 延伸后蛋白质磷酸化的降低，磷酸酶的隐式激活，例如 钙调神经素。我们的数据导致我们假设扩展培训，除了涉及新学习 机制也可以反对正常的重新溶解过程。我们建议这发生在同一 通过CA2+调节的突触沉积机制的电路。灭绝引起的突触沉积 据报道有条件的恐惧记忆，CAMKII和钙调神经蛋白信号的差异已有报道，但是 尚未检查与可卡因相关的记忆。这是使用目标中的方法组合 2＆3，我们将确定CAMKIIα是否通过S331磷酸化和钙调蛋白的激活是否抑制 磷酸酶，可以降低可卡因记忆强度，以减少通过增强的提示诱导的恢复原状 扩展和抑制重新溶解。我们还将确定这些信号通路是否直接 相互调节，并在相同或不同的途径中进行突触强度。确定机制 调节可卡因的记忆将导致预防预防治疗的新目标。