Patterns and neurocognitive consequences of opioid-alcohol polysubstance use

项目摘要 阿片酒精多物质使用(PSU)是一个临床相关的问题，因为它恶化了轨迹和 阿片类药物使用障碍的后果(例如，14-16%的阿片类药物过量还涉及酒精)。酒精和阿片类药物 单独使用与严重的神经行为后果有关，例如认知障碍，但它是 目前尚不清楚在阿片酒精PSU的这些领域中是否存在相加或协同损害。在……里面 为了确定阿片酒精PSU有害后果的潜在机制(例如 寻找毒品的动机，复发，认知)，啮齿动物模型是必要的。在这里，我们建议发展小说 基于人类阿片酒精多物质使用者的反向翻译数据的啮齿动物模型。因此，在这2- R61/R33阶段提案，我们将首先评估人类阿片类药物和酒精使用的时间模式，方面 按小时和按天使用，使用我们的新评估，多物质使用-时间模式 部分(PSU-TPS)。我们还将使用物质滥用模块5(SAM-5)来确定数量、频率、 和使用持续时间(QFD)以及使用障碍的存在。这些数据将用于定义PSU的集群 模式，基于使用的小时/天和天数/月，以及使用是顺序、并发还是 同时发生的。在相同的参与者中，认知能力将在基线和一年后进行评估。域名 感兴趣的包括工作和情景记忆、冲动、高风险决策和认知灵活性。我们 将在基线和一年后确定阿片类药物/酒精使用与认知之间的关系- 向上。我们还将比较PSU集群之间使用的不良后果，重点是使用的QFD， 符合DSM-V使用障碍和认知障碍标准的百分比。然后我们将回译 最常见的啮齿动物体内有害后果的PSU模式用于静脉注射的评估 阿片类药物自我给药，使用需求曲线分析寻找阿片类药物的动机，以及对阿片类药物的复发- 寻找。我们还将使用啮齿动物模型来直接测试阿片类药物和酒精使用以及多物质使用的作用 在这种认知障碍上，使用已经建立的评估相同领域的啮齿动物任务 在人类身上。我们还将评估PSU的两种模式是否会改变酒精和 阿片类药物。这项拟议的分两个阶段进行的研究汇集了各自领域的多学科专家团队 对现实世界阿片-酒精多物质使用的模式和后果进行新的评估 建立可促进该领域发展的转译动物模型。

Project Abstract Opioid-alcohol polysubstance use (PSU) is a clinically-relevant problem, as it worsens the trajectories and outcomes of opioid use disorder (e.g., 14-16% of opioid overdoses also involve alcohol). Both alcohol and opioid use alone are associated with significant neurobehavioral consequences, such as impaired cognition, but it is not currently known if there are additive or synergistic impairments in such domains in opioid-alcohol PSU. In order to determine the mechanisms underlying the deleterious consequences of opioid-alcohol PSU (e.g. motivation to seek drug, relapse, cognition), rodent models are necessary. Here, we propose to develop novel rodent models based on back-translated data from human opioid-alcohol polysubstance users. Thus, in this 2- phase R61/R33 proposal, we will first assess human temporal patterns of opioid and alcohol use, in terms of hour-by-hour and day-by-day use, using our novel assessment, the PolySubstance Use – Temporal Pattern Section (PSU-TPS). We will also use the Substance Abuse Module-5 (SAM-5) to determine quantity, frequency, and duration (QFD) of use and the presence of use disorders. These data will be used to define clusters of PSU patterns, based on hours/day and days/month of use, and whether use is sequential, concurrent, or simultaneous. In the same participants, cognition will be assessed at baseline and one year later. The domains of interest include working and episodic memory, impulsivity, risky decision-making, and cognitive flexibility. We will determine associations between opioid/alcohol use and cognition at both baseline and at the one year follow- up. We will also compare the adverse consequences of use between PSU clusters, with a focus on QFD of use, percent meeting DSM-V criteria for use disorder, and cognitive impairments. We will then back-translate the most prevalent PSU patterns with deleterious consequences into rodents for the assessment of intravenous opioid self-administration, motivation to seek opioids using demand curve analyses, and relapse to opioid- seeking. We will also use rodent models to directly test the role of opioid and alcohol use and polysubstance use on such cognitive impairments, using rodent tasks that have been established to assess the same domains as in humans. We will also assess whether the two patterns of PSU alter the pharmacokinetics of alcohol and opioids. This proposed 2-phase study brings together a multidisciplinary team of experts in their fields to conduct novel assessments of the patterns and consequences of real-world opioid-alcohol polysubstance use for the establishment of translational animal models that can advance the field.