权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/摘要物质使用障碍，影响美国约2010万人，的特征在于自愿吸毒转变为强迫性吸毒和吸毒行为，尽管有负面影响，结果，在禁欲期后仍然容易复发。虽然环境的影响被确定为风险因素，但在理解导致死亡的生物因素方面存在重大差距。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。以前的研究表明，脆性X智力低下蛋白（FMRP），一种RNA结合蛋白，调节突触可塑性，是可卡因诱导的纹状体（一个大脑区域）突触消除所必需的对奖励功能至关重要。此外，FMRP的缺失，无论是广泛的还是在腹侧纹状体（核）中， NAc），能够抑制可卡因诱导的行为，这些行为被认为是高血压的标志。成瘾相关风险本R36应用的主要目的是确定 FMRP促进静脉内可卡因的操作性自我给药和药物寻求的恢复行为基于已发表的和初步的数据，中心假设是FMRP正介导可卡因静脉自我给药和通过其活动的调节恢复药物寻求- 在NAc的D1受体（D1 R）表达细胞中调节的细胞凋亡相关蛋白（Arc）。这假设将在两个特定的目标进行测试，每个目标都利用有条件的击倒方法，广泛的自我给药试验，包括线索和药物诱导的恢复范例。目标1将确定FMRP是否通过其在细胞的特异性D1 R或D2 R细胞中的功能介导这些表型。 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，作为她在成瘾相关科学的职业生涯培训的一部分，深入了解FMRP介导药物相关行为的机制，提供关键方向用于未来的研究，旨在确定治疗干预的下游靶点。