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

此R21应用程序旨在确定神经、行为和药理学机制 人类可卡因成瘾患者与药物相关的记忆表达减弱。吸毒成瘾是一种慢性疾病 其中，先前与药物强化相关的提示(例如，管道)唤起了对 吸毒的经历。这些记忆助长了渴望，甚至在长时间的 禁欲。传统的线索暴露疗法旨在消除药物线索的刺激效应， 因此得到了广泛的应用。然而，这些疗法通常不能防止复发，这突显了 另类战略。这个探索性项目的目标是确定一种药物增强的学习- 基于行为的方法及其潜在的神经机制，最终可能成为目标 减少人类成瘾的渴求和复发。我们的行为方法，旨在干扰 可卡因使用障碍(ICUD)患者药物记忆的恢复建立在动物和人类行为的基础上 研究表明，在药物线索记忆消失前10分钟提取它们会导致持久的记忆 减轻线索诱导的寻药和渴求。因此，这种方法利用了尖端技术 研究记忆重新巩固的机制，这是一个依赖于时间的过程，在这个过程中，特定的 巩固的记忆在取回后不久就会变得短暂不稳定，使它们容易受到 破坏或加强。由于iCUD表现出学习和记忆以及潜在神经基质的缺陷， 我们将使用哌醋甲酯(mph，一种多巴胺激动剂)，从药理上加强这一行为方法。 作为一种认知增强剂，促进学习诱导的iCUD神经可塑性。公共卫生标准的选择是基于 ICUD的一系列神经成像研究，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。具体地说，在这个功能磁共振成像(FMRI)中 研究中，在受试者内安慰剂对照的双盲交叉设计中，口服MPH(20毫克)将是 在恢复药物线索记忆的过程中给予iCUD以达到峰值；除功能磁共振成像外 激活，皮肤电导反应(SCR，同时获得)将作为心理生理 内存修改指示器。SCR对药物线索记忆返回的干扰评估 而渴望将在核磁共振后的第二天进行。这个项目将描绘出一种 药物增强的行为方法减少药物记忆和对iCUD的渴望，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，这些新奇的疗法 后来有证据表明，这些方法可以改善iCUD的临床结果，这项探索性研究可能为 为了提高线索暴露疗法在减少线索诱导的渴求和复发方面的有效性，理想也 出于个人药物的目的。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。

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.