The synergy of methylphenidate-and reconsolidation-based extinction normalizes ventromedial prefrontal function in drug addiction

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2512310122
• 发表日期: 2025-11-11
• 页码: e2512310122
• 关键词: methylphenidate; cocaine; memory; Forgetting; ventromedial prefrontal cortex; ADRENERGIC-RECEPTOR BLOCKADE; MEMORY RECONSOLIDATION; COCAINE ADDICTION; dopamine; fear; amygdala; cortex; inhibition; humans; PROPRANOLOL

摘要

Drug-related memories can hinder abstinence goals in drug addiction. Promoting nondrugmemories via ventromedial prefrontal cortex (vmPFC)-and amygdala-guided extinctionyields mixed success. Postretrieval extinction (RE) destabilizes and updates memoriesduring reconsolidation, improving extinction. Supplementing RE, we tested methylphenidate(MPH), a dopamine agonist that promotes PFC-dependent learning and memory in cocaineuse disorder (CUD). In a proof-of-concept double-blind randomized clinical trialusing a within-subjects design, participants received oral MPH (20 mg) or placebobefore the retrieval of some of the conditioned stimuli (CS) (i.e., reminded CS+ vs.nonreminded CS+) followed by extinction; lab-simulated drug-seeking was measuredthe following day. Lower vmPFC activity following nonreminded CS+ (standardextinction) under placebo replicated the putative impairments in CUD; separately, RE (trend) and MPH conditions recruited the vmPFC, and RE's vmPFC-reliance correlatedwith drug-seeking only under placebo. Crucially, MPH-combined RE normalized cortico-limbicprocessing, bypassing the vmPFC and its amygdala connectivity. Pharmacologically-enhanced drug memory modulation may inform intervention development for addictionrecovery.