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: 10447976
• 负责人: Rita Z Goldstein
• 金额: $ 25.35万
• 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/10447976
• 关键词: Abstinence; Alcohols; Animals; Behavior Control; Behavioral; Cannabis; Chronic Disease; Cigarette Smoker; Clinical; Cocaine; Cocaine Dependence; Cocaine use disorder; Cognitive; Crossover Design; Cues; Development; Disease; Dopamine Agonists; Double-Blind Method; Drug Addiction; Drug usage; Emotional; Exhibits; Extinction (Psychology); Functional Magnetic Resonance Imaging; Future; Galvanic Skin Response; Goals; Gold; Heroin; Human; Impairment; Individual; Intervention; Knowledge; Lead; Learning; Magnetic Resonance Imaging; Measures; Medicine; Memory; Methods; Modification; Neurobiology; Neuronal Plasticity; Neurosciences; Nootropic Agents; Opioid; Oral; Outcome; Pharmaceutical Preparations; Pharmacology; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Psychopathology; Psychophysiology; Reaction; Relapse; Reporting; Research; Retrieval; Ritalin; Series; Substance Use Disorder; Testing; Time; Training; Traumatic Brain Injury; addiction; attenuation; base; behavioral pharmacology; behavioral study; blood oxygen level dependent; classical conditioning; cognitive enhancement; cognitive rehabilitation; cognitive training; conditioned fear; craving; design; drug of abuse; drug reinforcement; experience; imaging study; improved; improved outcome; memory process; neural circuit; neural correlate; neuroimaging; neuromechanism; novel; novel strategies; outcome prediction; prevent; relating to nervous system; remediation; response; substance use; 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.

该 R21 应用旨在确定促进神经、行为和药理学机制 人类可卡因成瘾中与药物相关的记忆表达减少。吸毒成瘾是一种慢性疾病 以前与药物强化相关的线索（例如管道）唤起了显着且普遍的记忆 吸毒经历。这些记忆会导致渴求，甚至在长期戒毒后也会导致旧病复发。 节制。传统的线索暴露疗法旨在消除药物线索的这些刺激作用 因此被广泛使用。然而，这些疗法通常不能防止复发，这突出表明需要 替代策略。这个探索性项目的目标是确定一种药理学增强学习- 基于行为方法及其潜在的神经机制，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 (iCUD) 个体的药物记忆恢复基于动物和人类行为 研究表明，在药物提示记忆消失前 10 分钟检索它们会导致持久的记忆 线索引起的药物寻求和渴望的减弱。因此，这种方法利用了尖端技术 研究记忆再巩固的机制，记忆再巩固是一个依赖于时间的过程，其中特定的 巩固的记忆在检索后不久就会变得短暂不稳定，使它们能够适应任何一种情况 破坏或加强。由于 iCUD 在学习和记忆以及潜在的神经基质方面表现出缺陷， 我们将使用哌醋甲酯（MPH，多巴胺激动剂）从药理学角度增强这种行为方法 作为认知增强剂，促进 iCUD 中学习诱导的神经可塑性。 MPH 的选择基于 iCUD 中的一系列神经影像研究，我们报告了功能（行为和神经）的正常化 其他相关的认知行为任务。具体来说，在功能磁共振成像 (fMRI) 中 研究中，在受试者内安慰剂对照双盲交叉设计中，口服 MPH（20 毫克）将 在药物提示记忆消失前的检索过程中给予 iCUD 使其达到峰值；除了功能磁共振成像 激活、皮肤电导反应（SCR，同时获得）将作为心理生理学 内存修改指标。通过 SCR 评估药物提示记忆恢复的干扰 MRI 的第二天将进行渴望测试。该项目将描述一个神经元的相关性 药理学增强行为方法可减少 iCUD 中的药物记忆和渴望，这可以 最终用于开发有效的线索暴露疗法。如果与标准疗法相比，这些新颖的疗法 后来证明这些方法可以改善 iCUD 的临床结果，这项探索性研究可能会铺平道路 提高线索暴露疗法在减少线索引起的渴望和复发方面的功效，也是理想的选择 用于个人医疗目的。这项基础研究的结果可以推广到其他类型的药物滥用 或行为成瘾。