Brain Development after Early-Life Antipsychotic Treatment

早期抗精神病治疗后的大脑发育

• 批准号: 10629613
• 负责人: MARK Edward BARDGETT
• 金额: $ 13.7万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629613
• 关键词: Adult; Affect; Age; Amphetamines; Antipsychotic Agents; Attention deficit hyperactivity disorder; Award; Basic Science; Behavioral; Bioinformatics; Biomedical Research; Brain; Brain region; Child; Childhood; Collaborations; Control Groups; Core Facility; Data; Development; Dextroamphetamine; Disease; Disruptive Behavior Disorder; Dopamine; Dopamine Agonists; Dopamine Receptor; Dose; Drug Exposure; Elderly; Environment; Exhibits; Extinction; FOS gene; Funding; Genetic; Genetic Transcription; Geographic Locations; Goals; Grant; Health Sciences; Hyperactivity; Immediate-Early Genes; Injections; Institution; Kentucky; Label; Laboratory Rat; Life; Long-Term Effects; Mental disorders; Mentors; Messenger RNA; Metabolic; Modification; Neurons; Neurosciences; Neurotransmitter Receptor; Nucleus Accumbens; Opioid; Outcome; Oxycodone; Paper; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Policy Maker; Population; Prosencephalon; Psychology; Publishing; Rattus; Reporting; Research; Research Project Grants; Research Support; Resources; Rewards; Risk; Risperidone; Science; Scientist; Series; Short-Term Memory; Students; Substance abuse problem; Synapses; Techniques; Technology; Time; Tissue Sample; Training; Transcript; Underrepresented Populations; United States; United States National Institutes of Health; Universities; Work; boys; college; conditioned place preference; conditioning; dopamine transporter; drug of abuse; experience; girls; high risk; mRNA Expression; member; model organism; neural; next generation; opioid overdose; opioid use; postnatal; programs; psychostimulant; response; transcriptome sequencing; undergraduate student

7. Project Summary/Abstract This is an application for a Support of Research Enhancement (SuRE) R16 award. These grants are intended to support small scale research projects at institutions like Northern Kentucky University that do not receive substantial NIH funding, with an additional emphasis on providing biomedical research experiences to students from groups traditionally underrepresented in biomedical and health science and enhancing the research environment at the university. Antipsychotic drugs (APDs) are widely used in children mainly as off-label treatments for a multitude of pediatric psychiatric disorders, despite the lack of basic research documenting their effects on later brain and behavioral function. One concern is that APD exposure during early brain development alters later sensitivity to drugs of abuse. Our previous NIH-funded research showed that adult rats administered the APD, risperidone, early in life are hyperactive, exhibit enhanced locomotor and rewarding responses to the psychostimulant, D- amphetamine, and display alterations in forebrain dopamine transporters and receptors. These data were generated by undergraduate students at NKU, many of whom served as first- or co- authors on published papers, and some of whom went on to pursue graduate study in psychology. Having ascertained that early-life risperidone modifies responses to psychostimulant drugs that directly target dopamine synapses, we now seek to determine if behavioral and neural sensitivity to other classes of drugs, such as opioids, that indirectly work though dopamine pathways is enhanced by early-life risperidone. The proposed work will ascertain whether behavioral, neural, and genetic responses to the opioid drug, oxycodone, are altered in adult rats administered risperidone early in life (daily injections from postnatal day 14-42). This issue is especially germane to NKU students since our geographic area is marked by relatively high rates of opioid use and overdose. Overall, the proposed research will address the following questions: 1) Does early-life APD administration enhance the rewarding effects of oxycodone during adulthood?, 2) Does early-life APD administration increase neural sensitivity to oxycodone in the forebrain during adulthood? and 3) Does early-life APD administration modify patterns of forebrain gene transcription induced by oxycodone during adulthood? The last aim will be achieved by collaborating with the nearby University of Louisville to quantify mRNA expression in tissue samples using next-generation RNA-Seq technology. A concomitant goal of this work will be to continue engaging NKU undergraduate students in the execution, analysis, and reporting of research. The proposed work will take advantage of training and pedagogical resources offered by NKU and the KY-INBRE program to enhance these experiences and, in turn, contribute to the overall research environment at NKU.

7. 项目总结/摘要 这是研究增强支持 (SuRE) R16 奖项的申请。这些补助金是 旨在支持北肯塔基大学等机构的小规模研究项目，这些项目不 获得大量 NIH 资助，并额外强调提供生物医学研究经验 来自传统上在生物医学和健康科学领域代表性不足的群体的学生，并提高 大学的研究环境。 抗精神病药物（APD）广泛用于儿童，主要作为多种疾病的超说明书治疗。 儿科精神疾病，尽管缺乏基础研究记录其对以后大脑和精神疾病的影响 行为功能。一个担忧是早期大脑发育过程中的 APD 暴露会改变后来的敏感性 滥用药物。我们之前 NIH 资助的研究表明，成年大鼠服用 APD、利培酮、 生命早期过度活跃，表现出增强的运动能力和对精神兴奋剂 D- 的奖励反应 安非他明，并显示前脑多巴胺转运蛋白和受体的改变。这些数据是 由 NKU 本科生创作，其中许多人是已发表的论文的第一作者或共同作者 论文，其中一些人继续攻读心理学研究生课程。 确定生命早期利培酮可以改变对精神兴奋药物的反应，从而直接影响 目标多巴胺突触，我们现在试图确定是否对其他类别的行为和神经敏感 生命早期的利培酮可以增强通过多巴胺途径间接发挥作用的药物，例如阿片类药物。 拟议的工作将确定对阿片类药物的行为、神经和遗传反应是否 羟考酮，在生命早期注射利培酮（从出生后每天注射）的成年大鼠中发生改变 14-42）。这个问题对 NKU 学生尤其重要，因为我们的地理区域相对来说是 阿片类药物使用率和用药过量率很高。总体而言，拟议的研究将解决以下问题：1） 生命早期 APD 给药是否会增强成年期羟考酮的奖励作用？, 2) 生命早期 APD 给药是否会增加儿童时期前脑对羟考酮的神经敏感性？ 成年？ 3) 生命早期 APD 给药是否会改变前脑基因转录模式 成年期间使用羟考酮诱发？最后一个目标将通过与附近的合作来实现 路易斯维尔大学使用下一代 RNA-Seq 量化组织样本中的 mRNA 表达 技术。这项工作的另一个目标是继续让 NKU 本科生参与 研究的执行、分析和报告。拟议的工作将利用培训和 NKU 和 KY-INBRE 项目提供的教学资源可增强这些体验，进而， 为 NKU 的整体研究环境做出贡献。