Memory reconsolidation interference as a therapeutic mechanism of action of the serotonergic psychedelic N,N-Dimethyltryptamine

过度饮酒和酒精使用障碍（AUD）是全球主要的精神健康问题（世界卫生组织，2018），但对这些疾病的有效治疗很少，并且仅在有限的亚群中使用（Mekonen et al.，2021年）。已经提出记忆再巩固干扰干预作为成瘾（米尔顿和Everitt，2012）和其他基于记忆的障碍如创伤后应激障碍和恐惧症（例如Saladin等人，2013; Brunet et al.，2008; Soeter & Kindt，2015）。记忆巩固干预旨在通过重新激活和破坏这些记忆并通过药物阻断或新信息干扰其重新巩固来削弱促进复发的适应不良奖励记忆痕迹（Dudai，2006）。虽然荟萃分析显示总体效果大小有利于记忆再巩固干预而不是控制程序（例如，沃尔什等人，最近，精神病学已经看到对迷幻药物（如裸盖菇素、二甲基色胺（DMT）和氯胺酮）的治疗潜力的研究有所增加（例如，Carhart-Harris等人，2021; D 'Souza等人，2022; Das等人，2019年）。初步研究表明，迷幻辅助干预措施可能是成瘾性疾病的一种有希望的治疗方法，可能比现有干预措施提供更大、更持久的疗效（Morgan等人，2017年）。然而，这一新兴的研究领域缺乏坚实的理论基础，也没有良好的对照研究来调查迷幻药物治疗效果的基本机制。记忆再巩固已被作为一种这样的机制提出（Fattore et al，2018; Feduccia and Mithoefer，2018; Daneluz et al，2022），然而，虽然表面上很吸引人，但还没有足够的测试来证明这种假设机制与多巴胺能致幻剂。如果再巩固-更新确实是致幻剂治疗效果的关键因素，这将对干预设计和优化产生重要影响。我的博士学位的目的有三个方面：1）系统地量化假定记忆再巩固干扰研究中的方法学差异，以了解效果异质性的关键来源，并为方法的协调提供指导。2)为了在人类可测量的尺度上了解多巴胺能致幻剂的“神经可塑性”机制，使用DMT作为UNITy项目中的模型药物（见下文），这是有史以来最大，最丰富，最严格的DMT-fMRI试验。3)探讨酒精记忆再巩固干扰作为DMT在危险饮酒者中的作用机制;为成瘾性疾病的进一步研究提供框架。

Excessive drinking and alcohol use disorder (AUD) are major mental health problems worldwide (World Health Organisation, 2018), yet the effective treatments for these conditions are few and are of use in limited subpopulations (Mekonen et al., 2021). Memory reconsolidation interference interventions have been proposed as a potential novel treatment for addictive (Milton and Everitt, 2012) and other memory-based disorders such as PTSD and phobia (e.g. Saladin et al., 2013; Brunet et al., 2008; Soeter & Kindt, 2015). Memory Reconsolidation interventions aim to weaken relapse-promoting maladaptive reward memory traces by reactivating and destabilizing these memories and interfering with their reconsolidation via pharmacological blockade or novel information (Dudai, 2006). Whilst meta-analyses have shown an overall effect size favoring memory reconsolidation interventions over control procedures (e.g. Walsh et al., 2018), both the methodology and results of individual trials are plagued by inconsistencies.Recently, psychiatry has seen an uptick in research into the therapeutic potential of psychedelic drugs, such as psilocybin, Dimethyltryptamine (DMT), and ketamine (e.g. Carhart-Harris et al., 2021; D'Souza et al., 2022; Das et al., 2019). Preliminary research shows that psychedelic-assisted interventions may be a promising treatment for addictive disorders, potentially offering both greater and longer-lasting efficacy than existing interventions (Morgan et al., 2017). However, this nascent area of research suffers from a lack of solid theoretical foundation and no well-controlled studies investigating the fundamental mechanisms of psychedelic drugs' therapeutic effects. Memory reconsolidation has been forwarded as one such mechanism (Fattore et al, 2018; Feduccia and Mithoefer, 2018; Daneluz et al, 2022), yet while superficially appealing, there has been no adequate test of this hypothetical mechanism with serotonergic psychedelics. If reconsolidation-update is indeed a key player in the therapeutic effect of psychedelics, this will have important implications for intervention design and optimization.The purpose of my PhD is threefold: 1) To systematically quantify methodological variability in studies of putative memory reconsolidation interference to understand key sources of effect heterogeneity and offer guidance for harmonization of methods. 2) To understand 'neuroplastic' mechanisms of serotonergic psychedelics at human-measurable scales, using DMT as a model drug in the UNITy project (see below), the largest, richest, most rigorous DMT-fMRI trial ever conducted. 3) To investigate alcohol memory reconsolidation interference as a mechanism of action of DMT in hazardous drinkers; providing a framework for further work in addictive disorders.