Circuit-specific molecular mechanisms in fentanyl use and relapse

芬太尼使用和复发的电路特异性分子机制

• 批准号: 10503495
• 负责人: Megan Elizabeth Fox
• 金额: $ 24.9万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10503495
• 关键词: Abstinence; Attention; Automobile Driving; Award; Back; Behavior; Brain Diseases; Complex; Data; Development; Dopamine; Dopamine D1 Receptor; Drug Addiction; Drug Exposure; Drug abuse; Drug usage; Fentanyl; Fluorescent in Situ Hybridization; Funding; Genetic Transcription; In Situ Hybridization; Incidence; Individual; Intake; Learning; Mentors; Molecular; Molecular Biology; Molecular Profiling; Molecular Target; Mus; National Institute of Drug Abuse; Neurobiology; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Receptor; Overdose; Pathway interactions; Periodicity; Persons; Pharmaceutical Preparations; Phase; Physiological; Play; Procedures; Relapse; Research; Rewards; RiboTag; Ribosomes; Role; Scanning; Self Administration; Synapses; Testing; Therapeutic; Training; Translating; United States; Ventral Tegmental Area; Viral; Virus; Work; addiction; bridge program; cell type; cost; designer receptors exclusively activated by designer drugs; dopaminergic neuron; drug of abuse; drug relapse; experience; gamma-Aminobutyric Acid; health economics; insight; knock-down; mouse model; novel; novel therapeutics; opioid abuse; opioid mortality; opioid use; overexpression; prescription opioid abuse; programs; response; reward circuitry; synthetic opioid; tool; training opportunity; transcriptome sequencing; translatome

Project Summary/Abstract Drug addiction is a complex brain disorder that takes an enormous toll on individual and economic health. Current drug-abuse treatments are not effective in all individuals, and many recovering addicts continue to relapse. Drug exposure usurps normal reward circuit function, including the connections between the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Both NAc and VTA undergo molecular and physiological changes in response to drugs of abuse. The VTA sends dopaminergic projections to the NAc, and the NAc sends GABAergic projections back to the VTA. Activity in NAc and VTA are key for driving drug use and are heavily implicated in drug relapse. Numerous studies have established the importance of the dopaminergic VTA to NAc projection, however the connection from NAc back to VTA is understudied in drug addiction. The incidence of opioid use, opioid addiction, and death from opioid overdose are at an unprecedented high. In this K99/R00 Pathway to Independence Award, I aim to identify how NAc projections to the VTA influence opioid use and relapse. Using a mouse model of fentanyl self-administration, I have collected preliminary data showing NAc neurons that project to VTA control fentanyl seeking after forced abstinence. In this study, I intend to utilize intersectional circuit manipulation and cutting-edge molecular biology to investigate the molecular mechanisms by which NAc projections to VTA control fentanyl intake and relapse. During the mentored phase, in Aim 1, I will learn operant self-administration procedures and combine them with chemogenetic manipulation to assess the necessity of NAc terminals in VTA in fentanyl use and relapse. In Aim 2, I will learn RNAseq and in situ hybridization to profile molecular adaptations in specific VTA neurons after fentanyl self-administration. During the independent phase, in Aim 3, I will use novel viral constructs to assess the role of molecular manipulations in specific VTA neurons in fentanyl use and relapse. In Aim 4, I will assess the role of fentanyl and molecular manipulations on dopamine release in the NAc using fast-scan cyclic voltammetry. Together, the research proposed in this Pathway to Independence Award will elucidate molecular mechanisms in the NAc-VTA circuit driving opioid use and relapse, while simultaneously providing me with the tools necessary for establishing an independent research program that bridges molecular biology, circuit manipulation, operant behavior, and voltammetry for examining addiction.

项目概要/摘要 毒瘾是一种复杂的脑部疾病，对个人和经济健康造成巨大损失。当前的 药物滥用治疗并非对所有人都有效，许多正在康复的成瘾者还会继续复吸。药品 暴露篡夺了正常的奖赏回路功能，包括腹侧被盖区之间的连接 (VTA) 和伏隔核 (NAc)。 NAc 和 VTA 均经历分子和生理变化 对滥用药物的反应。 VTA 向 NAc 发送多巴胺能投射，NAc 发送 GABA 能投射 投影回 VTA。 NAc 和 VTA 的活性是驱动药物使用的关键，并且与 药物复发。大量研究已经确定了多巴胺能 VTA 对 NAc 投射的重要性， 然而，NAc 与 VTA 之间的联系在药物成瘾方面尚未得到充分研究。 阿片类药物使用、阿片类药物成瘾以及阿片类药物过量导致的死亡发生率空前高。在 在这个 K99/R00 独立之路奖中，我的目的是确定 NAc 对 VTA 的预测如何影响阿片类药物 使用和复发。使用芬太尼自我给药的小鼠模型，我收集了初步数据，显示 投射到 VTA 的 NAc 神经元控制强制戒酒后寻求芬太尼。在这项研究中，我打算利用 交叉电路操作和尖端分子生物学研究分子机制 通过 NAc 对 VTA 的预测来控制芬太尼的摄入和复发。在指导阶段，在目标 1 中，我将 学习操作性自我管理程序并将其与化学遗传学操作相结合以评估 VTA 中 NAc 终端在芬太尼使用和复发中的必要性。在目标 2 中，我将学习 RNAseq 和 in situ 杂交以分析芬太尼自我给药后特定 VTA 神经元的分子适应性。期间 独立阶段，在目标 3 中，我将使用新型病毒构建体来评估分子操作的作用 芬太尼使用和复发中特定 VTA 神经元的影响。在目标 4 中，我将评估芬太尼和分子药物的作用 使用快速扫描循环伏安法操纵 NAc 中的多巴胺释放。一起，研究 独立之路奖中提出的方案将阐明 NAc-VTA 回路中的分子机制 推动阿片类药物的使用和复发，同时为我提供建立阿片类药物所需的工具 连接分子生物学、电路操纵、操作行为和 用于检查成瘾性的伏安法。