Ceceli Ahmet O, King Sarah G, Drury K Rachel, McClain Natalie, Gray John, Dassanayake Priyanthi S, Newcorn Jeffrey H, Schiller Daniela, Alia-Klein Nelly, Goldstein Rita Z
Icahn School of Medicine at Mount Sinai.
medRxiv. 2025 Apr 30:2025.04.29.25326658. doi: 10.1101/2025.04.29.25326658.
Drug-related memories can hinder abstinence goals in drug addiction. Promoting non-drug memories via ventromedial prefrontal cortex- (vmPFC) and amygdala-guided extinction yields mixed success. Post-retrieval extinction (RE) destabilizes and updates memories during reconsolidation, improving extinction. Supplementing RE, we tested methylphenidate (MPH), a dopamine-agonist that promotes PFC-dependent learning and memory in cocaine use disorder (CUD). In an Early Phase 1 double-blind randomized clinical trial using a within-subjects design, participants received oral MPH (20 mg) or placebo before the retrieval of some of the conditioned stimuli (i.e., reminded CS+ vs. non-reminded CS+) followed by extinction; lab-simulated drug-seeking was measured the following day.
Lower vmPFC activity following non-reminded CS+ (standard extinction) under placebo replicated the putative impairments in CUD; separately, RE (trend) and MPH conditions recruited the vmPFC, and RE's vmPFC-reliance correlated with drug-seeking only under placebo. Crucially, MPH-combined RE normalized cortico-limbic processing, bypassing the vmPFC and its amygdala connectivity.
Pharmacologically-enhanced drug memory modulation may inform intervention development for addiction recovery.
与药物相关的记忆会阻碍药物成瘾者的戒断目标。通过腹内侧前额叶皮质（vmPFC）和杏仁核引导的消退来促进非药物记忆，其效果喜忧参半。检索后消退（RE）在重新巩固过程中会破坏记忆并对其进行更新，从而改善消退效果。作为对RE的补充，我们测试了哌甲酯（MPH），这是一种多巴胺激动剂，可促进可卡因使用障碍（CUD）中依赖前额叶皮质的学习和记忆。在一项采用受试者内设计的1期早期双盲随机临床试验中，参与者在检索一些条件刺激（即提示的CS+与未提示的CS+）之前接受口服MPH（20毫克）或安慰剂，随后进行消退；次日测量实验室模拟的觅药行为。
在安慰剂条件下，未提示的CS+（标准消退）后vmPFC活性降低，这重现了CUD中假定的损伤；另外，RE（有趋势）和MPH条件激活了vmPFC，并且仅在安慰剂条件下，RE对vmPFC的依赖与觅药行为相关。至关重要的是，MPH联合RE使皮质-边缘系统处理正常化，绕过了vmPFC及其与杏仁核的连接。
药物增强的药物记忆调节可能为成瘾康复的干预发展提供信息。
