Modulation of protracted opioid withdrawal by dorsal raphe dynorphin neurons

中缝背侧强啡肽神经元对长期阿片类药物戒断的调节

• 批准号: 10505724
• 负责人: Matthew B Pomrenze
• 金额: $ 15.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505724
• 关键词: Abstinence; Address; Advisory Committees; Anhedonia; Award; Behavior; Behavioral; Behavioral Model; Brain; Brain region; COVID-19 pandemic; Chronic; Data; Disease; Dopamine; Dorsal; Dynorphins; Economics; Emotional; Exhibits; Fiber; Genetic; Goals; Human; Impairment; Injections; Knock-out; Knockout Mice; Knowledge; Learning; Maps; Mediating; Mental Depression; Mentors; Mentorship; Modeling; Morphine; Mus; Nerve; Neurons; Neuropeptides; Nucleus Accumbens; Opioid; Overdose; Pathogenesis; Pathway interactions; Phase; Photometry; Population; Procedures; Receptor Activation; Relapse; Research; Rewards; Risk; Role; Self Administration; Serotonin; Social Behavior; Social Controls; Social isolation; Stress; Techniques; Testing; Training; Withdrawal; Withdrawal Symptom; base; behavior test; behavioral impairment; cell type; cost; craving; dopaminergic neuron; dorsal raphe nucleus; drug withdrawal; emotional symptom; improved; in vivo; insight; kappa opioid receptors; monoamine; mouse model; neural circuit; neurochemistry; neuromechanism; opioid epidemic; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; optogenetics; overdose death; pre-clinical; preference; prevent; programs; receptor expression; relapse risk; remifentanil; reward circuitry; sensor; social; social deficits; therapeutic development; tool

Project summary Opioid use disorder (OUD) is a chronic relapsing disorder that has cost the U.S. more than $1 trillion in 2017 alone. While initially driven by brain reward circuits, opioid consumption increasingly engages stress-related neural circuits that drive maladaptive emotional states. During the abstinent weeks, months, and years following opioid use, the risk of relapse is increased by emotional symptoms, such as social avoidance, depression, and opioid cravings. Similarly, tendencies to self-isolate during periods of protracted opioid withdrawal increase the risk of lethal overdose. The rapid escalation of opioid overdoses in the U.S. reflects the need for more data on neural mechanisms underlying protracted opioid withdrawal. The neuropeptide dynorphin and kappa opioid receptors (KOR) contribute to stress, aversion, and behavioral consequences of withdrawal. While evidence suggests that KOR effects may be due to modulation of dopamine and serotonin release in the nucleus accumbens (NAc), the brain regions and neural mechanisms mediating KOR control of opioid withdrawal remain a critical gap in knowledge. In this K99/R00 pathway to independence award, I aim to identify mechanisms by which KORs mediate changes in behavior during withdrawal. Using a mouse model of chronic, non-contingent morphine exposure, I have collected preliminary data indicating that 1) KOR activity in the NAc controls social avoidance and anhedonia produced during protracted withdrawal and 2) a population of dynorphin-producing neurons in the dorsal raphe nucleus, but not dynorphin neurons in the NAc itself, mediate the same effects. During the mentored phase, in Aim 1, I will learn to perform in vivo optogenetic procedures and fiber photometry recordings to characterize the role of dorsal raphe dynorphin neuron projections to the NAc in withdrawal behaviors. In Aim 2, I will expand on the model of non-contingent injections and establish a new model of remifentanil self-administration and examine relapse behavior during protracted withdrawal. I will also test changes in social and depression-like behaviors after self-administration. In the independent phase, in Aim 3, I will use my training from the K99 phase to combine optogenetics and fiber photometry recordings of dorsal raphe dynorphin inputs to the NAc with remifentanil self-administration and relapse testing. In Aim 4, I will expand on additional preliminary data collected with non-contingent injections showing that KOR expression in serotonin and dopamine neurons is critical for social avoidance and depression-like behaviors, respectively. I will use fiber photometry and fluorescent sensors of dopamine and serotonin to record release in the NAc during protracted withdrawal testing. In addition, I will examine dopamine and serotonin dynamics in the self-administration model developed in Aim 2 by testing mice with the same cell-type specific KOR knockouts and performing photometry recordings of release in the NAc. Overall, this proposal will investigate key mechanisms underlying protracted opioid withdrawal with a combination of advanced techniques, while simultaneously providing me with the tools necessary for establishing an independent research program aimed at dissecting the pathogenesis of OUD.

项目概要 阿片类药物使用障碍 (OUD) 是一种慢性复发性疾病，2017 年给美国造成的损失超过 1 万亿美元 独自的。虽然阿片类药物最初是由大脑奖励回路驱动的，但它的消费越来越多地与压力相关 驱动适应不良情绪状态的神经回路。在禁欲后的几周、几个月和几年里 使用阿片类药物后，情绪症状会增加复发的风险，例如社交回避、抑郁和 对阿片类药物的渴望。同样，在长期阿片类药物戒断期间自我隔离的倾向会增加 致命过量的风险。美国阿片类药物过量的迅速升级反映出需要更多的数据 长期阿片类药物戒断的神经机制。神经肽强啡肽和卡帕阿片类药物 受体（KOR）会导致压力、厌恶和戒断行为后果。虽然有证据 表明 KOR 效应可能是由于细胞核中多巴胺和血清素释放的调节所致 伏隔核（NAc），介导 KOR 控制阿片类药物戒断的大脑区域和神经机制仍然存在 知识上的重大差距。在通往独立奖的 K99/R00 途径中，我的目标是通过以下方式确定机制： 哪些 KOR 可以调节戒断期间的行为变化。使用慢性、非偶然的小鼠模型 吗啡暴露，我收集了初步数据，表明 1) NAc 中的 KOR 活动控制着社交 长期戒断过程中产生的回避和快感缺失以及 2) 产生强啡肽的群体 中缝背核中的神经元，但 NAc 本身中的强啡肽神经元，不会介导相同的作用。 在目标 1 的指导阶段，我将学习执行体内光遗传学程序和光纤光度测定 记录以表征中缝背侧强啡肽神经元投射到 NAc 在戒断中的作用 行为。在目标 2 中，我将扩展非偶然注入模型，并建立一个新的模型 瑞芬太尼自我给药并检查长期停药期间的复发行为。我也来测试一下 自我管理后社交和抑郁样行为的变化。在独立阶段，在目标 3 中，我 将利用我在 K99 阶段的训练来结合中缝背侧的光遗传学和光纤光度测量记录 通过瑞芬太尼自我给药和复发测试将强啡肽输入 NAc。在目标 4 中，我将扩展 通过非偶然注射收集的额外初步数据显示血清素中的 KOR 表达 和多巴胺神经元分别对社交回避和抑郁样行为至关重要。我将使用纤维 多巴胺和血清素的光度测定和荧光传感器，用于记录长时间内 NAc 中的释放 戒断测试。此外，我将检查自我管理模型中的多巴胺和血清素动态 通过测试具有相同细胞类型特异性 KOR 敲除的小鼠并进行光度测定，在 Aim 2 中开发 NAc 中发布的录音。总体而言，该提案将调查长期存在的关键机制 结合先进技术的阿片类药物戒断，同时为我提供工具 建立旨在剖析 OUD 发病机制的独立研究计划是必要的。