Long-term effects of early-life antipsychotic drug treatment

生命早期抗精神病药物治疗的长期影响

• 批准号: 8179930
• 负责人: MARK Edward BARDGETT
• 金额: $ 40.62万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8179930
• 关键词: Accounting; Address; Adult; Adverse effects; Affect; Age; Animal Experimentation; Antipsychotic Agents; Attention; Auditory; Autistic Disorder; Award; Basic Science; Behavior; Behavioral; Brain; Brain region; Child; Childhood; Collaborations; Communities; Corpus striatum structure; Data; Development; Disease; Dopamine; Dopamine Agonists; Dopamine Receptor; Dorsal; Drug Exposure; Drug Prescriptions; Drug effect disorder; Drug usage; Drug user; Elements; Exhibits; Exposure to; FDA approved; Female; Foundations; Funding; Gene Expression; Hyperactive behavior; Impulsivity; Institution; Interdisciplinary Study; Kentucky; Laboratory Rat; Life; Link; Long-Term Effects; Measurable; Measures; Mental disorders; Microelectrodes; Motor Activity; Neurosciences; Neurotransmitter Receptor; Neurotransmitters; Nucleus Accumbens; Policy Maker; Population; Prefrontal Cortex; Principal Investigator; Prosencephalon; Protocols documentation; Psychological reinforcement; Psychopharmacology; Psychotropic Drugs; Rattus; Relative (related person); Reporting; Research; Research Personnel; Research Support; Risperidone; Sensorimotor functions; Speed; Staging; Symptoms; System; Technology; Testing; Time; United States National Institutes of Health; Universities; Work; atypical antipsychotic; autism spectrum disorder; base; clinical efficacy; cognitive function; college; critical period; discounting; early life exposure; experience; male; neurochemistry; neuron development; postnatal; prepulse inhibition; programs; receptor; receptor binding; research study; serotonin receptor; young adult

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.

描述（由申请人提供）：本申请代表 AREA R15 奖项的提交。这些奖项旨在支持涉及 NIH 资金有限的机构的本科生的研究。本研究的目的是开始确定生命早期接触抗精神病药物 (APD) 的长期行为影响。过去 15 年来，APD 在儿科人群中的使用量增加了一倍，这一现象引起了科学界和国家媒体的广泛关注。这种增加是在相对缺乏记录生命早期 APD 暴露对以后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 作用的研究将成为填补这一空白的重要第一步。在成年大鼠中，长期 APD 治疗引起的持续受体阻断会导致大脑多巴胺功能发生代偿性但短暂的变化，这一点已得到证实。相比之下，目前尚无研究机构确定 APD 治疗对发育中大鼠的长期影响。我们的假设是，由于这种治疗的时间安排，生命早期接触 APD 可能会导致大脑多巴胺功能发生补偿性但永久性的变化，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 天起每天接受非典型 APD 利培酮治疗的大鼠在年轻时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，当前的应用程序将确定生命早期利培酮暴露对成年期间运动活动和感觉运动门控的影响是否存在关键时期，以及生命早期利培酮是否会提高这些行为对多巴胺的敏感性激动剂，增强冲动，并扰乱成年期前脑多巴胺的释放。拟议的工作将作为申请人建立旨在阐明生命早期 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有关发育过程中长期 APD 治疗的长期后果的关键信息。最后，拟议的研究将作为一种工具，让本科生参与精神药理学、发育神经科学和神经化学方面独特的综合研究经验。 公共健康相关性：尽管相对缺乏记录此类药物暴露对以后大脑和行为功能影响的基础研究，但在过去 15 年中，儿科人群中抗精神病药物的使用量增加了一倍。本研究的目的是确定实验室大鼠生命早期接触抗精神病药物的长期行为影响。这项研究将为研究人员、政策制定者和从业者提供有关开发过程中长期抗精神病药物治疗的长期后果的关键信息，此外还增强北肯塔基大学本科生在神经科学方面的研究经验。