Targeting neural, behavioral and pharmacological mechanisms of drug memories in cocaine addiction

针对可卡因成瘾药物记忆的神经、行为和药理学机制

• 批准号: 10707903
• 负责人: Rita Z Goldstein
• 金额: $ 21.13万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10707903
• 关键词: Abstinence; Alcohols; Animals; Association Learning; Behavior Control; Behavioral; Cannabis; Chronic Disease; Cigarette Smoker; Clinical; Cocaine; Cocaine Dependence; Cocaine use disorder; Cognitive; Corpus striatum structure; Crossover Design; Cues; Development; Disease; Dopamine Agonists; Double-Blind Method; Drug Addiction; Drug usage; Emotional; Exhibits; Extinction; Functional Magnetic Resonance Imaging; Future; Galvanic Skin Response; Goals; Heroin; Human; Impairment; Impulsivity; Individual; Intervention; Knowledge; Learning; Magnetic Resonance Imaging; Measures; Medicine; Memory; Methods; Modification; Neural Inhibition; Neurobiology; Neuronal Plasticity; Neurosciences; Nootropic Agents; Opioid; Oral; Outcome; Pharmaceutical Preparations; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Psychopathology; Psychophysiology; Rattus; Reaction; Relapse; Reporting; Research; Retrieval; Ritalin; Schizophrenia; Series; Stroke; Substance Use Disorder; Testing; Time; Training; Traumatic Brain Injury; addiction; attenuation; behavioral study; blood oxygen level dependent; cognitive enhancement; cognitive rehabilitation; cognitive training; conditioned fear; craving; design; drug of abuse; drug reinforcement; experience; forgetting; imaging study; improved; improved outcome; memory consolidation; memory process; neural; neural circuit; neural correlate; neuroimaging; neuromechanism; novel; novel strategies; outcome prediction; pharmacologic; prevent; relapse prevention; remediation; response; success

This R21 application aims to identify the neural, behavioral, and pharmacological mechanisms promoting diminished expression of drug-related memories in human cocaine addiction. Drug addiction is a chronic disorder where cues previously associated with drug reinforcement (e.g., pipe) evoke salient and pervasive memories of the drug experience. These memories contribute to craving, precipitating relapse even after long periods of abstinence. Traditional cue-exposure therapies aimed at extinguishing these provoking effects of drug cues have therefore been widely used. However, these therapies do not usually prevent relapse, highlighting the need for alternative strategies. The goal of this exploratory project is to identify a pharmacologically-enhanced learning- based behavioral approach and its underlying neural mechanisms that could ultimately be targeted for decreasing craving and relapse in human addiction. Our behavioral approach, designed to interfere with the return of drug memories in individuals with cocaine use disorders (iCUD), builds on animal and human behavioral studies showing that retrieval of drug-cue memories 10 min before their extinction results in long-lasting attenuation of cue-induced drug-seeking and craving. This approach thus takes advantage of cutting-edge research on the mechanisms underlying memory reconsolidation, a time-dependent process in which specific consolidated memories become transiently unstable shortly after their retrieval, making them amenable to either disruption or strengthening. Since iCUD exhibit deficits in learning and memory and underlying neural substrates, we will enhance this behavioral approach pharmacologically, using methylphenidate (MPH, a dopamine agonist) as a cognitive enhancer to promote learning-induced neural plasticity in iCUD. Choice of MPH is based on a series of neuroimaging studies in iCUD where we reported normalization of function (behavioral and neural) on other relevant cognitive-behavioral tasks. Specifically, in this functional magnetic resonance imaging (fMRI) study, in a within-subjects placebo-controlled double-blind cross-over design, oral MPH (20 mg) will be administered to iCUD to peak during the retrieval of a drug-cue memory before extinction; in addition to fMRI activations, skin conductance responses (SCR, acquired simultaneously) will serve as the psychophysiological indicators of memory modification. Assessments of interference with the return of drug-cue memories via SCR and craving will be conducted the day following MRI. This project will delineate the neural correlates of a pharmacologically-enhanced behavioral approach to decrease drug memories and craving in iCUD, which could be ultimately used to develop effective cue-exposure therapies. If, compared to standard therapies, these novel approaches are later shown to improve clinical outcome in iCUD, this exploratory study may pave the way towards enhancing the efficacy of cue-exposure therapy in reducing cue-induced craving and relapse, ideal also for personal medicine purposes. Results from this basic study could generalize to other types of drugs of abuse or to behavioral addictions.

此R21应用旨在确定促进的神经，行为和药理机制 人类可卡因成瘾中与药物相关记忆的表达减少。吸毒成瘾是一种慢性疾病 以前与药物加固相关的提示（例如，管道）引起了显着和普遍的记忆 毒品体验。这些记忆有助于渴望，即使很长一段时间 节制。旨在消除这些发动机提示的传统提示暴露疗法已有 因此被广泛使用。但是，这些疗法通常不会阻止复发，强调了需要 替代策略。这个探索性项目的目的是确定具有药理增强的学习 - 基于行为方法及其基本的神经机制，最终可以针对 减少人类成瘾的渴望和复发。我们的行为方法，旨在干扰 可卡因使用障碍的人（ICUD）的毒品记忆返回，建立在动物和人类行为上 研究表明，在灭绝之前10分钟的药物记忆的检索导致持久 提示引起的寻求毒品和渴望的衰减。因此，这种方法利用了尖端 研究重新溶解的机制的研究，这是一个时间依赖的过程，其中特定的过程 巩固记忆在取回后不久就会瞬间不稳定，使它们适合任何一个 破坏或加强。由于ICUD在学习和记忆和潜在的神经底物方面表现出缺陷，所以 我们将使用哌醋甲酯（MPH，多巴胺激动剂）在药理学上增强这种行为方法 作为认知增强子，可以促进ICUD中学习引起的神经可塑性。 MPH的选择是基于 ICUD中的一系列神经影像学研究，我们报告了功能（行为和神经）的归一化（行为和神经） 其他相关的认知行为任务。具体而言，在这种功能性磁共振成像中（fMRI） 研究，在受试者内安慰剂控制的双盲跨界设计中，口服MPH（20 mg）将是 在灭绝前的药物记忆中检索期间，施用至峰峰；除了fMRI 激活，皮肤电导反应（SCR，同时获得）将作为心理生理学 内存修改的指标。评估通过SCR的毒品证明记忆回报的干扰评估 渴望将在MRI之后的第二天进行。该项目将描述一个神经相关性 药理学增强的行为方法，以减少ICUD的药物记忆和渴望，这可能 最终用于开发有效的提示暴露疗法。如果与标准疗法相比，这些小说 后来显示出方法可以改善ICUD的临床结果，这项探索性研究可能会为 为了增强提示暴露疗法在减少提示引起的渴望和复发方面的功效，也理想 出于个人医学目的。这项基础研究的结果可能会推广到其他类型的滥用药物 或行为成瘾。