Brain Development after Early-Life Antipsychotic Treatment

7.项目总结/摘要 这是一份支持研究增强（SuRE）R16奖的申请。这些赠款 旨在支持像北方肯塔基州大学这样的机构的小规模研究项目， 获得大量的NIH资金，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， 大学的研究环境。 抗精神病药物（APD）广泛用于儿童，主要作为多种药物的标签外治疗。 儿童精神疾病，尽管缺乏基础研究记录其对后来的大脑和 行为功能一个令人担忧的问题是，在早期大脑发育过程中暴露于APD会改变后来对 滥用药物。我们之前的NIH资助的研究表明，成年大鼠给予APD，利培酮， 在生命的早期是多动的，表现出增强的运动和奖励反应的精神兴奋剂，D- 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 由NKU的本科生产生，其中许多人是第一作者或共同作者， 他们中的一些人继续攻读心理学研究生。 已经确定，早期生活利培酮改变反应的精神兴奋剂药物，直接 针对多巴胺突触，我们现在试图确定是否行为和神经敏感性，以其他类别的 通过多巴胺途径间接起作用的药物，如阿片类药物，在生命早期被利培酮增强。 拟议中的工作将确定是否行为，神经和遗传反应的阿片类药物， 羟考酮在生命早期给予利培酮（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学生来说尤其重要，因为我们的地理区域的特点是相对 阿片类药物使用和过量的高比率。总体而言，拟议的研究将解决以下问题：1） 早期APD给药是否能增强成年期羟考酮的奖励效应？，（二） 早期APD给药是否会增加在治疗期间前脑对羟考酮的神经敏感性 成年？以及3）早期APD给药是否改变了前脑基因转录的模式 羟考酮引起的吗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定量组织样本中的mRNA表达 技术.这项工作的一个伴随目标将是继续让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计划提供的教学资源，以增强这些经验，反过来， 为NKU的整体研究环境做出贡献。

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.