Reconsolidation and Memory Interference Toolkit (REMIT): Identifying how to destabilise and overwrite maladaptive alcohol memories.

重新巩固和记忆干扰工具包（REMIT）：确定如何破坏和覆盖适应不良的酒精记忆。

• 批准号: MR/M007006/1
• 负责人: Sunjeev Kamboj
• 金额: $ 60.84万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM007006%2F1
• 关键词: Reconsolidation; Memory; Interference; Toolkit; REMIT

Alcohol Use Disorder (AUD) is a global disease challenge which incurs vast health and social costs. Current treatments fail in the long term as they do not address the aberrant memory processes that maintain drinkers' susceptibility to relapse even after years of abstinence. This quiescent susceptibility is due to Maladaptive Motivational Memories (MMMs) that accompany and support alcohol abuse. Associations formed between environmental 'cues' and drinking imbue the cues with motivational properties that cause cravings, alcohol seeking and relapse when similar cues are re-encountered in the environment. Recent evidence shows that memories can be permanently altered by manipulating a process called 'reconsolidation.' This process is initiated under certain circumstances, causing a retrieved memory to become destabilised. During the 'reconsolidation window' - the interval between destabilisation and restabilisation - the memory is rendered malleable. These findings suggest an exciting opportunity for treating alcohol problems by weakening the MMMs at the heart of AUD.In rodents, MMMs can be destabilised using a reminder of previous learning (e.g. a tone that previously signalled drug availability). Since restabilisation requires activity at certain brain receptors (especially NMDARs), it can be blocked pharmacologically. If this occurs, the animal later behaves as if the memory association had been 'erased' and drug seeking stops. Available NMDA antagonists - like ketamine - could similarly be used to block restabilisation of MMMs in humans. It may also be possible to 'overwrite' MMMs behaviourally, by training adaptive new associations while MMMs are unstable. This type of procedure would also be expected to reduce cue-induced craving and drinking.While these strategies are promising, there are key issues which must be resolved before MMM-modification can be developed for addiction. These are i) that MMMs only destabilise under certain conditions and ii) we cannot yet measure memory destabilisation directly. The critical first step towards developing MMM-modifying treatments for AUD is therefore to develop methods for reliably destabilising MMMs and metrics for measuring this. The primary factor determining memory destabilisation at retrieval is a mismatch between the outcomes predicted by a memory association (e.g. drinking alcohol) and actual outcome (e.g. the drink is withheld), also called a 'prediction error' (PE).This PE enables memory destabilisation when new information about the availability or effects of alcohol coincides with memory retrieval, allowing the memory to be updated with new information. This project aims to identify robust procedures for destabilising alcohol-MMMs and measuring this destabilisation. To do this we will examine the effects of i) blocking restabilisation using the NMDAR antagonist, ketamine and ii) overwriting destabilised MMMs so that they no longer promote drinking.In both studies, we manipulate the mismatch between expected and actual drinking outcomes during retrieval of alcohol-MMMs in harmful drinkers. We predict that unexpected information about alcohol availability or value when recalling alcohol-MMMs will cause their destabilisation. In Study I, we aim to block re-stabilisation with ketamine, weakening the alcohol-MMM's ability to activate alcohol seeking and drinking. In Study II, we will use a behavioural procedure to over-write destabilised alcohol-MMMs by training associations between the alcohol cues and unpleasant outcomes (a very bitter drink and aversive pictures) in the reconsolidation window. This procedure should update the effect of alcohol cues from pro- to anti-consummatory. Both interventions should result in reduced alcohol-seeking and drinking.If one or both of the procedures are successful, they will have significant potential as clinical treatments for AUD, although wider application to other addictions and psychological disorders is also possible.

酒精使用障碍（AUD）是一项全球性疾病挑战，造成巨大的健康和社会成本。目前的治疗方法从长期来看是失败的，因为它们没有解决异常的记忆过程，这种记忆过程使饮酒者即使在戒酒多年后也容易复发。这种静态易感性是由于伴随和支持酒精滥用的不适应动机记忆（MMMs）。环境“线索”和饮酒之间形成的联系赋予了这些线索动机属性，这些属性导致了对酒精的渴望、酒精寻求和在环境中再次遇到类似线索时的复发。最近的证据表明，通过操纵一个被称为“再巩固”的过程，记忆可以被永久地改变。这个过程是在某些情况下启动的，导致检索到的记忆变得不稳定。在“再巩固窗口”（不稳定和再稳定之间的间隔）期间，记忆变得具有可塑性。这些发现表明，通过削弱澳元核心的MMMs来治疗酒精问题是一个令人兴奋的机会。在啮齿类动物中，MMMs可以通过先前学习的提醒（例如，先前表示药物可用的音调）来破坏稳定。由于再稳定需要某些脑受体（尤其是NMDARs）的活动，因此可以通过药物阻断。如果发生这种情况，动物之后的行为就会像记忆关联被“抹去”一样，药物寻找也会停止。可用的NMDA拮抗剂——如氯胺酮——同样可以用于阻止人类MMMs的再稳定。当mm不稳定时，通过训练自适应的新关联，也可能在行为上“覆盖”mm。这类程序也有望减少线索引起的渴望和饮酒。虽然这些策略很有希望，但在开发出用于成瘾的mmm修饰之前，必须解决一些关键问题。它们是i) mm只在某些条件下不稳定ii)我们还不能直接测量内存不稳定。因此，开发针对澳元的mm修正疗法的关键第一步是开发可靠地破坏mm稳定性的方法和测量方法。决定提取时记忆不稳定的主要因素是记忆关联预测的结果（例如饮酒）与实际结果（例如不喝酒）之间的不匹配，也称为“预测误差”（PE）。当有关酒精的可用性或影响的新信息与记忆检索相吻合时，这种PE使记忆不稳定，从而使记忆更新为新信息。本项目旨在确定稳定酒精- mm的可靠程序，并测量这种不稳定。为此，我们将研究i)使用NMDAR拮抗剂氯胺酮阻断再稳定的影响，ii)覆盖不稳定的MMMs，使其不再促进饮酒。在这两项研究中，我们在有害饮酒者的酒精- mmms检索过程中操纵了预期和实际饮酒结果之间的不匹配。我们预测，当回忆酒精- mm时，有关酒精可得性或价值的意外信息将导致它们的不稳定。在研究1中，我们的目标是用氯胺酮阻止再稳定，削弱酒精- mmm激活酒精寻找和饮酒的能力。在研究II中，我们将使用一种行为程序，通过训练酒精线索与再巩固窗口中令人不快的结果（非常苦的饮料和令人厌恶的图片）之间的联系，来覆盖不稳定的酒精- mm。这一程序应将酒精提示的作用从促促性更新为抗促促性。这两种干预措施都应减少寻求酒精和饮酒。如果一种或两种方法都成功，它们将有很大的潜力作为AUD的临床治疗，尽管更广泛地应用于其他成瘾和心理障碍也是可能的。

项目成果

Ketamine Can Reduce Harmful Drinking by Pharmacologically Rewriting Drinking Memories

氯胺酮可以通过药理学重写饮酒记忆来减少有害饮酒

• DOI: 10.1016/j.biopsych.2020.02.498
• 发表时间: 2020
• 期刊: Biological Psychiatry
• 影响因子: 10.6
• 作者: Das R

The effects of cognitive reappraisal following retrieval-procedures designed to destabilize alcohol memories in high-risk drinkers.

• DOI: 10.1007/s00213-015-4164-y
• 发表时间: 2016-03
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Hon T;Das RK;Kamboj SK
• 通讯作者: Kamboj SK

Modulation of naturalistic maladaptive memories using behavioural and pharmacological reconsolidation-interfering strategies: A systematic review and meta-analysis of clinical and 'sub-clinical' studies

使用行为和药理再巩固干扰策略调节自然适应不良记忆：临床和“亚临床”研究的系统回顾和荟萃分析

• DOI: 10.1101/282293
• 发表时间: 2018
• 作者: Walsh K

A Prediction Error-driven Retrieval Procedure for Destabilizing and Rewriting Maladaptive Reward Memories in Hazardous Drinkers.

• DOI: 10.3791/56097
• 发表时间: 2018-01-05
• 期刊: Journal of visualized experiments : JoVE
• 作者: Das RK;Gale G;Hennessy V;Kamboj SK
• 通讯作者: Kamboj SK

The Subjective Response to Nitrous Oxide is a Potential Pharmaco-Endophenotype for Alcohol Use Disorder: A Preliminary Study with Heavy Drinkers.

• DOI: 10.1093/ijnp/pyw063
• 发表时间: 2017-04-01
• 期刊: The international journal of neuropsychopharmacology
• 作者: Walsh K;Das RK;Kamboj SK
• 通讯作者: Kamboj SK