Mechanisms Regulating Cocaine Memory Strength

项目总结/摘要 成瘾性疾病对个人和社会都是一个巨大的负担。不幸的是， 有效的治疗方法，部分原因是与药物相关的记忆的持续存在， 复发因此，最近的研究集中在寻找减少药物相关性的强度的方法上。 防止复发的记忆。记忆强度可以通过以下方式降低： 提示和药物通过消除或通过抑制记忆在提醒事件后的重新巩固。两 策略在临床前和临床模型中是有效的，但在某些情况下， 相反，由于无意中增强了再巩固或抑制了再巩固， 灭绝为了解决这个问题，我们分析了蛋白质磷酸化的变化后， 记忆经历消退与重新巩固，以确定信号级联， 记忆过程，或者理想地以相反的方向调节这两个过程。识别对方 信号事件可以使治疗方法的发展，既增强灭绝， 重新巩固，减少与药物相关的记忆的强度，推动复吸。我们的初步数据 强烈表明基底外侧杏仁核（BLA）中相反的Ca 2+相关信号传导事件介导了 与自我服用可卡因相关的记忆的再巩固与消失。我们将扩大我们 确定拟议研究目标1中的相反信号事件，包括增加 分析的蛋白质，扩展分析的时间过程，并将分析扩展到女性。此外，委员会认为， 我们将对我们最初研究的令人兴奋的发现进行跟踪，这些发现包括：1）鉴定出一种新的 Ca 2 + -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 通过消除和减少在重新巩固的功能，以抑制激酶活性，和2）一般 消退后蛋白质磷酸化减少，涉及磷酸酶的激活，如 钙调神经磷酸酶我们的数据使我们假设，除了涉及新的学习， 机制，也可以反对正常的再固结过程。我们建议，这发生在同一个 通过Ca 2+调节的突触去电位机制。熄灭诱发的突触去增强 条件性恐惧记忆中CaMKII和钙调神经磷酸酶信号的差异已经被报道，但 还没有被检查过可卡因相关记忆因此，使用Aims中的方法组合 图2&3中，我们将确定是否通过S331磷酸化和钙调神经磷酸酶的激活来抑制CaMKIIα 磷酸酶，可以降低可卡因记忆强度，以减少线索诱导的恢复，通过增强 消退和抑制再巩固。我们还将确定这些信号通路是否直接 在相同或不同的通路中相互调节和突触强度。确定机制 调节可卡因记忆将导致复发预防治疗开发的新靶点。

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.