FMRP in the striatum: mechanisms of early drug reward

项目摘要/摘要 在美国，影响大约2010万人的物质使用障碍的特点是 自愿吸毒转变为强制寻求和吸毒行为，尽管存在负面影响，但这种行为仍在继续 而且在禁欲一段时间后仍容易复发。尽管环境的影响 已被确定为危险因素，但对导致癌症的生物因素的理解存在重大差距。 发展成物质使用障碍，限制我们提供有效和持久治疗的能力。 先前的研究表明，脆性X智力低下蛋白(FMRP)是一种与RNA结合的蛋白质，可以 调节突触可塑性，是可卡因诱导的纹状体突触消除所必需的，纹状体是脑区 对奖励功能至关重要。此外，FMRP的丢失，无论是广泛的还是在腹侧纹状体(核) Vacumbens；NAC)，能够抑制可卡因诱导的行为，这些行为被认为是 与成瘾相关的风险。此R36应用程序的主要目标是确定 FMRP促进可卡因的手术自我给药和恢复寻求毒品 行为。基于已发表和初步数据的中心假设是，FMRP起积极的调节作用 可卡因静脉注射自我给药，并通过其对活动的调节恢复寻找毒品- 调节细胞骨架相关蛋白(Arc)在表达D1R的NAC细胞中。这 假设将在两个特定目标中进行测试，每个目标都使用有条件的击倒方法和 广泛的自我给药分析，包括线索和药物诱导的恢复范式。目标1将 确定FMRP是否通过其在D1R或D2R细胞中的功能调节这些表型 NAC，而AIM 2将确定FMRP对Arc的调节是否有助于这些表型。这部作品 将完成申请者的论文，作为她在成瘾相关科学领域职业生涯培训的一部分， 深入了解FMRP调节药物相关行为的机制，提供关键方向 用于未来旨在确定治疗干预下游靶点的研究。

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.