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

这项R21的应用旨在确定神经，行为和药理学机制，促进 人类可卡因成瘾中与药物相关的记忆表达减少。毒瘾是一种慢性疾病 其中先前与药物强化相关的线索（例如，管道）唤起对以下事物的突出和普遍的记忆： 毒品的经验。这些记忆有助于渴望，即使在长时间的 禁欲传统的线索暴露疗法旨在消除这些药物线索的刺激作用， 因此被广泛使用。然而，这些疗法通常不能预防复发，突出了需要 替代战略。这个探索性项目的目标是确定一个药理学增强学习- 基于行为的方法及其潜在的神经机制，最终可以针对 减少人类上瘾的渴望和复发。我们的行为方法，旨在干扰 可卡因使用障碍（iCUD）患者的药物记忆恢复，建立在动物和人类行为的基础上， 研究表明，在药物提示记忆消失前10分钟的恢复会导致长期的 减弱线索诱导的药物寻求和渴望。因此，这种方法利用了尖端的 记忆再巩固是一个时间依赖性的过程， 巩固的记忆在恢复后不久就变得短暂不稳定，使它们容易受到以下两种情况的影响： 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，一种多巴胺激动剂）加强这种行为方法， 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 在iCUD中进行的一系列神经影像学研究中，我们报告了功能（行为和神经）正常化， 其他相关的认知行为任务。具体来说，在这项功能性磁共振成像（fMRI） 研究中，在受试者内安慰剂对照双盲交叉设计中，将口服MPH（20 mg） 给予iCUD，以在消退前恢复药物提示记忆期间达到峰值;除了fMRI外， 激活，皮肤电导反应（SCR，同时获得）将作为心理生理学的 记忆修改的迹象通过SCR评估对药物提示记忆恢复的干扰 和渴望将在MRI后的第二天进行。这个项目将描绘神经相关的一个 药理学增强的行为方法，以减少药物记忆和渴望在iCUD，这可能 最终用于开发有效的线索暴露疗法。如果与标准疗法相比， 这些方法后来被证明可以改善iCUD的临床结局，这项探索性研究可能会铺平道路 为了提高线索暴露疗法在减少线索诱导的渴望和复发方面的功效， 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滥用药物 或行为成瘾。

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.