FMRP in the striatum: mechanisms of early drug reward

纹状体中的 FMRP：早期药物奖励机制

基本信息

批准号：
10379954
负责人：
Jessica Huebschman
金额：
$ 5.22万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379954
关键词：
Abstinence Affect Bacterial Artificial Chromosomes Behavior Biological Biological Assay Biological Factors Brain region Cells Cocaine Corpus striatum structure Cues Cytoskeleton DRD2 gene Data Development Disease Dopamine D1 Receptor Dose Drug Exposure FMR1 Food Future Goals Impairment Individual Infusion procedures Intravenous Knockout Mice Learning LoxP-flanked allele Mediating Memory Mission Modeling Mus National Institute of Drug Abuse Nucleus Accumbens Pharmaceutical Preparations Phenotype Prevention Proteins Publishing RNA-Binding Proteins Receptor Signaling Regulation Relapse Rewards Risk Risk Factors Role Science Scientist Self Administration Specificity Substance Use Disorder Substance abuse problem Synapses Synaptic plasticity Testing Therapeutic Intervention Training Training Support Transgenic Animals Translations United States Ventral Striatum Virus Work addiction base brain circuitry career cell type cocaine self-administration conditioned place preference drug development drug reward drug seeking behavior insight intravenous administration knock-down next generation overexpression protein expression protein function reinforcer small hairpin RNA targeted treatment

项目摘要

Project Summary/Abstract Substance use disorders, affecting approximately 20.1 million individuals in the U.S., are characterized by a shift in voluntary drug-taking to compulsive drug-seeking and -taking behaviors, which persist despite negative consequences and remain prone to relapse after periods of abstinence. Though environmental influences have been identified as risk factors, there are major gaps in understanding of biological factors that contribute to the development of substance use disorders, limiting our ability to provide effective and lasting treatments. Previous work suggests that the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates synaptic plasticity, is required for cocaine-induced synapse elimination in the striatum, a brain region critical to reward function. Moreover, loss of FMRP, either broadly or in the ventral striatum (nucleus accumbens; NAc), is capable of dampening cocaine-induced behaviors that are considered indicative of higher addiction-related risk. The main objective of this R36 application is to determine the mechanism by which FMRP facilitates operant self-administration of intravenous cocaine and reinstatement of drug-seeking behavior. The central hypothesis, based on published and preliminary data, is that FMRP positively mediates cocaine intravenous self-administration and reinstatement of drug-seeking via its regulation of the activity- regulated cytoskeleton-associated protein (Arc) in D1-receptor (D1R) expressing cells of the NAc. This hypothesis will be tested in two specific aims, each utilizing conditional knockdown approaches and an extensive self-administration assay that includes cue- and drug-induced reinstatement paradigms. Aim 1 will determine whether FMRP mediates these phenotypes via its function in specifically D1R or D2R cells of the NAc, while Aim 2 will determine whether FMRP’s regulation of Arc contributes to these phenotypes. This work will complete the applicant’s dissertation, as part of her training for a career in addiction-related science, provide insight into the mechanism by which FMRP mediates drug-related behaviors, providing critical direction for future studies aimed at identifying downstream targets for therapeutic intervention.

项目摘要/摘要在美国影响约2010万个人的药物使用障碍的特征是自愿吸毒向强迫性毒品和诱惑行为转移，尽管持续负面后果并在节制期间仍然容易接力。尽管环境影响有被确定为危险因素，了解生物学因素有主要差距物质使用障碍的发展，限制了我们提供有效和持久治疗的能力。先前的工作表明，脆弱的X智力低下蛋白（FMRP）是一种RNA结合蛋白，该蛋白调节突触可塑性，是可卡因诱导的纹状体中消除突触所必需的对奖励功能至关重要。此外，FMRP的丢失，无论是宽大还是在腹侧纹状体（核）伏伏; NAC），能够污染可卡因诱导的行为，这些行为被认为是较高的与成瘾有关的风险。该R36应用的主要目的是确定 FMRP的收藏夹操作静脉可卡因的自我管理和恢复毒品寻求药物行为。基于已发布和初步数据的中心假设是FMRP积极介导可卡因静脉内自我给药和恢复毒品的恢复，通过调节活性 - 在D1受体（D1R）表达NAC细胞中，调节的细胞骨架相关蛋白（ARC）。这假设将以两个具体的目的进行检验，每种都采用条件敲低方法和一个包括提示和药物诱导的恢复范式在内的广泛自我管理测定法。目标1意志确定FMRP是否在特定的D1R或D2R细胞中介导了这些表型 NAC，而AIM 2将确定FMRP对ARC的调节是否有助于这些表型。这项工作将完成申请人的论文，作为她在与成瘾有关的科学职业培训的一部分，提供有关FMRP介导与药物相关行为的机制的见解，提供了关键方向对于未来的研究，旨在确定治疗干预的下游靶标。