Fluoxetine: Sensitive Ages and Genotypes for Adverse Effects in Juvenile Monkeys

氟西汀：对幼猴产生不良影响的敏感年龄和基因型

• 批准号: 8107413
• 负责人: MARI S GOLUB
• 金额: $ 54.81万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107413
• 关键词: 12 year old; 3 year old; 4 year old; Address; Adolescent; Adverse effects; Affect; Affective; Age; Animal Model; Animals; Area; Attention; Autopsy; Basic Science; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Benefits and Risks; Brain; Cerebrospinal Fluid; Child; Childhood; Clinical Research; Cognitive; Communities; Computers; Control Groups; Dendritic Spines; Desire for food; Development; Disease; Dose; Drug Kinetics; Drug usage; Emotional; Equilibrium; Fluoxetine; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genotype; Goals; Growth; Hippocampus (Brain); Human; Knowledge; Literature; Long-Term Effects; Longitudinal Studies; Macaca mulatta; Methods; Modeling; Monitor; Monkeys; Monoamine Oxidase A; Oral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Placebos; Plasma; Population; Prefrontal Cortex; Primates; Psychotropic Drugs; Puberty; Regulation; Rewards; Rodent; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Short-Term Memory; Signal Transduction; Sleep; Staging; Structure; Subgroup; Synapses; System; Testing; Therapeutic; Toxic effect; Vertebral column; Walkers; base; behavior test; brain morphology; child depression; cognitive function; dentate gyrus; executive function; experience; indexing; infancy; juvenile animal; monoamine; nonhuman primate; response; selective attention; social; touchscreen

DESCRIPTION (provided by applicant): The biomedical literature has documented increasing use of psychoactive drugs in childhood behavior disorders and there is public concern over this issue. This application uses the rhesus monkey (1 to 4 years of age) as a juvenile animal model to: 1. test the hypothesis that the serotonin reuptake inhibitor fluoxetine influences activity and affective behavior during dosing at the juvenile stage of brain development. Information to identify a fluoxetine dose similar to human therapy will be provided by an initial pharmacokinetic study of plasma fluoxetine/norfluoxetine with a pharmacodynamics component to quantify serotonin in cerebrospinal fluid, a sensitive index in previous human and nonhuman primate studies. The affective behavior tests include some used in children (reward delay) as well as behaviors regulated by the serotonin system in monkeys (social intruder). Activity monitoring will conducted with actimeters. 2. identify alterations in brain morphology that could signal interference with normal juvenile brain development, specifically the proliferation and pruning of dendritic spine synapses. Daily oral fluoxetine will be given from 1 to 3 years of age (approximately 4 to 12 years of age in children). A placebo will be administered exclusively to a separate control group. Potential long-term effects will be assessed in all monkeys after discontinuation of dosing using an automated cognitive test battery. Dendritic spine synapse numbers in hippocampus (CA1, CA3, dentate gyrus) and prefrontal cortex (Walker area 46) will be studied at 4 years of age, one year after termination of dosing. This assessment is relevant to one of the most important components of childhood brain development, synaptic pruning. 3. determine whether some children may be more sensitive to these changes than others based on their genetic makeup. Colony-wide genetic screening at our primate center (CNPRC) allows selection of subgroups of monkeys with low and high activity MAOA gene polymorphisms. MAOA metabolizes serotonin, as well as other monoamines, and human populations have a similar distribution of low and high activity polymorphisms. Findings from this study, integrated with clinical studies and experience, can help guide safe use of fluoxetine in children. PUBLIC HEALTH RELEVANCE: This project studies fluoxetine, a drug approved for use in children for depression and obsessive-compulsive disease, in a juvenile animal model. We will determine whether fluoxetine changes affective (emotional) behavior and late childhood brain development, and determine whether some children may be more sensitive than others based on their genetic makeup. This study will help guide safe use of fluoxetine in children.

描述（由申请人提供）：生物医学文献记录了越来越多的精神活性药物用于儿童行为障碍，公众对此问题表示关注。本申请使用恒河猴（1至4岁）作为幼年动物模型以：1.检验以下假设：5-羟色胺再摄取抑制剂氟西汀在大脑发育的青少年阶段给药期间影响活动和情感行为。将通过血浆氟西汀/去甲氟西汀的初始药代动力学研究提供用于确定与人体治疗相似的氟西汀剂量的信息，该研究具有定量脑脊液中5-羟色胺的药效学组分，这是既往人体和非人灵长类动物研究中的敏感指标。情感行为测试包括一些用于儿童（奖励延迟）以及猴子（社会入侵者）中由血清素系统调节的行为。将使用活动计进行活动监测。2.确定大脑形态学的改变，可能会干扰正常的青少年大脑发育，特别是树突棘突触的增殖和修剪。1 - 3岁儿童（儿童约4 - 12岁）每日口服氟西汀。安慰剂将仅给予单独的对照组。将使用自动认知测试组合在所有猴中评估停药后的潜在长期影响。将在4岁时（给药终止后1年）研究海马（CA 1、CA 3、齿状回）和前额叶皮层（步行者区46）中的树突棘突触数量。这种评估与儿童大脑发育最重要的组成部分之一--突触修剪有关。3.根据他们的基因组成，确定一些孩子是否比其他孩子对这些变化更敏感。在我们的灵长类动物中心（CNPRC）进行的全群体遗传筛查允许选择具有低活性和高活性MAOA基因多态性的猴子亚组。MAOA代谢5-羟色胺以及其他单胺，并且人类群体具有相似的低活性和高活性多态性分布。本研究的结果，结合临床研究和经验，可以帮助指导儿童安全使用氟西汀。 公共卫生相关性：本项目在青少年动物模型中研究氟西汀，氟西汀是一种被批准用于儿童抑郁症和强迫症的药物。我们将确定氟西汀是否会改变情感（情绪）行为和儿童晚期大脑发育，并确定是否有些儿童可能比其他儿童更敏感，基于他们的基因组成。本研究将有助于指导儿童安全使用氟西汀。