Patterns and neurocognitive consequences of opioid-alcohol polysubstance use

项目摘要 阿片类酒精多物质使用（PSU）是一个临床相关的问题，因为它的轨迹， 阿片样物质使用障碍的结果（例如，14-16%的阿片类药物过量也涉及酒精）。酒精和阿片类药物 单独使用与显著的神经行为后果有关，如认知受损，但它是 目前尚不清楚在阿片样物质-醇PSU中的这些结构域中是否存在加和性或协同性损伤。在 为了确定阿片样物质-酒精PSU的有害后果的潜在机制（例如， 寻求药物的动机、复发、认知），啮齿动物模型是必要的。在这里，我们建议开发新的 啮齿动物模型基于人类阿片类酒精多物质使用者的反向翻译数据。因此，在这2- 根据R61/R33阶段的建议，我们将首先评估阿片类药物和酒精使用的人类时间模式， 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， 和持续时间（QFD）的使用和使用障碍的存在。这些数据将用于定义PSU群集 模式，基于使用的小时/天和天/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，将在基线和一年后评估认知。的域 感兴趣的包括工作记忆和情景记忆、冲动性、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联- 起来我们还将比较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。然后我们将反向翻译 最普遍的PSU模式，对啮齿动物产生有害后果，用于评估静脉内 阿片类药物自我给药，使用需求曲线分析寻求阿片类药物的动机，以及阿片类药物复发- 寻找我们还将使用啮齿动物模型直接测试阿片类药物和酒精使用以及多种物质使用的作用 在这种认知障碍，使用啮齿动物的任务，已建立评估相同的领域， 在人类身上。我们还将评估PSU的两种模式是否会改变酒精的药代动力学， 阿片类药物这项拟议的2阶段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的新评估 建立可促进该领域发展的转化动物模型。

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.