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

描述（由申请人提供）：生物医学文献记录了儿童行为障碍中越来越多地使用精神活性药物，这一问题引起了公众的关注。本应用程序使用恒河猴（1至4岁）作为幼年动物模型：1。验证5 -羟色胺再摄取抑制剂氟西汀在大脑发育的少年阶段剂量影响活动和情感行为的假设。确定与人类治疗相似的氟西汀剂量的信息将通过血浆氟西汀/去甲氟西汀的初始药代动力学研究提供，其药效学成分可量化脑脊液中的血清素，这是先前人类和非人类灵长类动物研究中的一个敏感指标。情感行为测试包括一些用于儿童的测试（奖励延迟），以及由猴子血清素系统调节的行为（社会入侵者）。活动监测将使用活动计进行。2. 识别可能干扰正常青少年大脑发育的大脑形态学变化，特别是树突棘突触的增殖和修剪。1至3岁（儿童约4至12岁）每日口服氟西汀。安慰剂将被单独给予一个对照组。在停止给药后，将使用自动认知测试电池评估所有猴子的潜在长期影响。4岁时，即终止给药一年后，研究海马（CA1、CA3、齿状回）和前额皮质（Walker区46）的树突棘突触数量。这项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，确定是否有些孩子对这些变化比其他孩子更敏感。在我们的灵长类中心（CNPRC）进行全种群遗传筛选，可以选择具有低活性和高活性MAOA基因多态性的猴子亚群。MAOA代谢5 -羟色胺，以及其他单胺，在人群中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，可以帮助指导氟西汀在儿童中的安全使用。

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.