Long-term effects of early-life antipsychotic drug treatment

描述（由申请人提供）：该申请代表了R15领域奖项的提交。这些奖项旨在支持在NIH资金有限的机构中涉及本科生的研究。本研究的目的是开始定义早期接触抗精神病药物（APDs）的长期行为影响。在过去15年中，儿科人群中apd的使用翻了一番，这一现象引起了科学界和国家媒体的相当大的关注。这种增加是在相对缺乏记录早期接触APD对后期大脑和行为功能影响的基础研究的情况下发生的。对实验室大鼠APD作用的研究将是填补这一空白的重要的第一步。在成年大鼠中，长期APD治疗引起的持续受体阻断导致脑多巴胺功能的代偿性但短暂的变化已经得到了很好的证实。相比之下，目前还没有研究确定APD治疗对发育中的大鼠的长期影响。我们的假设是，由于这种治疗的时机，早期接触apd可能会导致大脑多巴胺功能的代偿性永久性变化，这种变化会持续到成年期。我们自己的初步研究表明，从出生后14 - 42天，每天服用非典型APD利培酮的大鼠，在成年后表现出感觉运动门控缺陷和持续的运动过度活跃——这些行为与前脑多巴胺功能有关。在这些数据和我们的假设的指导下，当前的应用将确定是否存在早期利培酮暴露对成年期运动活动和感觉运动门控的影响的关键时期，以及早期利培酮是否会提高这些行为对多巴胺激动剂的敏感性，增强冲动性，并破坏成年期前脑多巴胺释放。拟议的工作将作为申请人建立旨在阐明早期APD治疗效果的研究计划的基础。反过来，这将为研究人员、政策制定者和从业者提供关于APD在发展过程中长期治疗的长期后果的关键信息。最后，建议的研究将作为一种媒介，让本科生参与精神药理学，发育神经科学和神经化学的独特和综合研究经验。

DESCRIPTION (provided by applicant): This application represents a submission for an AREA R15 award. These awards are intended to support research that involves undergraduates at institutions that have limited NIH funding. The purpose of this research is to begin defining the long-term behavioral effects of early-life exposure to antipsychotic drugs (APDs). Over the past 15 years, the use of APDs in pediatric populations has doubled - a phenomenon that has garnered considerable attention in the scientific community and national media. This increase has occurred in the relative absence of basic research documenting the effects of early-life APD exposure on later brain and behavioral function. Studies of APD action in laboratory rats would serve as a significant first step in filling this void. It has been well established in adult rats that continuous receptor blockade caused by long-term APD treatment leads to compensatory yet transient changes in brain dopamine function. In contrast, there is currently no body of research that has ascertained the long-term effects of APD treatment in developing rats. Our hypothesis is that, due to the timing of such treatment, early-life exposure to APDs may engender compensatory yet permanent changes in brain dopamine function that persist through adulthood. Our own preliminary research has shown that rats treated daily with the atypical APD, risperidone, from postnatal days 14 - 42 exhibit sensorimotor gating deficits and persistent locomotor hyperactivity as young adults - behaviors linked to forebrain dopamine function. Guided by these data and our hypothesis, the current application will determine if there are critical periods for the effects of early-life risperidone exposure on locomotor activity and sensorimotor gating during adulthood, and whether early-life risperidone heightens the sensitivity of these behaviors to dopamine agonists, enhances impulsivity, and disrupts forebrain dopamine release in adulthood. The proposed work would act as a foundation for the applicant to establish a program of research aimed at elucidating the effects of early-life APD treatment. In turn, this would provide researchers, policy-makers, and practitioners with critical information regarding the long-term consequences of prolonged APD treatment during development. Finally, the proposed research will be used as a vehicle to engage undergraduates in unique and integrative research experiences in psychopharmacology, developmental neuroscience, and neurochemistry. PUBLIC HEALTH RELEVANCE: The use of antipsychotic drugs in pediatric populations has doubled over the past 15 years despite the relative absence of basic research documenting the effects of such drug exposure on later brain and behavioral function. The purpose of this research is to ascertain the long-term behavioral effects of early-life exposure to antipsychotic drugs in laboratory rats. This research will provide researchers, policy-makers, and practitioners with critical information regarding the long-term consequences of prolonged antipsychotic drug treatment during development, in addition to enhancing research experiences in neuroscience among college undergraduates at Northern Kentucky University.