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

基本信息

批准号：
10541911
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
项目类别：
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/10541911
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 Genetic Transcription Home 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 Pathway interactions Periodicity Persons Pharmaceutical Preparations Phase Physiological Play Postdoctoral Fellow 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 fentanyl seeking fentanyl self-administration fentanyl use gamma-Aminobutyric Acid genetic manipulation health economics insight knock-down mouse model novel novel therapeutics opioid abuse opioid mortality opioid use overdose death overexpression prescription opioid abuse programs response reward circuitry synthetic opioid tool training opportunity transcriptome sequencing translatome

项目摘要

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.

项目摘要/摘要吸毒成瘾是一种复杂的脑部疾病，对个人和经济健康造成了巨大损失。当前的滥用药物的治疗对所有个体都不是有效的，许多康复的成瘾者仍在继续复发。药品曝光篡夺正常奖励电路功能，包括腹侧段区域之间的连接（VTA）和伏隔核（NAC）。 NAC和VTA都经历了分子和生理变化对滥用药物的反应。 VTA向NAC发送多巴胺能预测，NAC发送GABAEGIC 投影回到VTA。 NAC和VTA的活动是驱动吸毒的关键，并且很大程度上涉及药物复发。许多研究确定了多巴胺能VTA对NAC投影的重要性，然而，从NAC回到VTA的连接在药物成瘾中被研究了。阿片类药物使用，阿片类药物成瘾和阿片类药物过量死亡的发病率是空前的高度。在我的K99/R00独立奖奖，我的目标是确定NAC对VTA的预测如何影响阿片类药物使用和复发。使用芬太尼自我管理的鼠标模型，我收集了显示的初步数据在强迫戒酒后，向VTA控制芬太尼的NAC神经元。在这项研究中，我打算使用交叉电路操纵和尖端的分子生物学研究分子机制 NAC对VTA控制芬太尼的摄入和复发的投影。在指导阶段，在AIM 1中，我将学习操作者的自我管理程序，并将其与化学发生操作结合在一起，以评估芬太尼使用和复发中NAC终端的必要性。在AIM 2中，我将学习RNASEQ和原位芬太尼自我给药后特定VTA神经元的分子适应性杂交。期间独立阶段，在AIM 3中，我将使用新颖的病毒构建体来评估分子操纵的作用在芬太尼使用和复发中的特定VTA神经元中。在AIM 4中，我将评估芬太尼和分子的作用使用快速扫描的循环伏安法在NAC中释放多巴胺的操纵。一起研究在此获得独立奖励的途径中提出的将阐明NAC-VTA电路中的分子机制驱动阿片类药物的使用和复发，同时为我提供建立必要的工具独立研究计划，桥接分子生物学，电路操纵，操作行为和伏安法检查成瘾。