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

描述(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在儿童行为障碍中的使用，这一问题引起了公众的关注。本应用使用恒河猴(1至4岁)作为幼年动物模型：1.验证5-羟色胺重摄取抑制剂氟西汀在大脑发育幼年阶段给药影响活动和情感行为的假设。确定类似于人类治疗的氟西汀剂量的信息将通过对血浆氟西汀/去氟西汀进行的初步药代动力学研究提供，该研究带有药效学成分，以量化脑脊液中的5-羟色胺，这是以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(奖赏延迟)，以及猴子受5-羟色胺系统调节的行为(社交入侵者)。活动监测将使用活动计进行。2.识别大脑形态的变化，这些变化可能会干扰正常的青少年大脑发育，特别是树突突触的增殖和修剪。每天口服氟西汀的年龄为1至3岁(儿童约为4至12岁)。安慰剂将专门用于单独的对照组。在停止使用自动认知测试电池给药后，将对所有猴子的潜在长期影响进行评估。停止给药一年后，将在4岁时研究海马(CA1、CA3、齿状回)和前额叶皮质(Walker区46区)中树突棘突触的数量。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.根据孩子的基因组成，确定他们是否比其他孩子对这些变化更敏感。在我们的灵长类中心(CNPRC)进行的群体范围的遗传筛选可以选择MAOA基因低活性和高活性的猴子亚群。MAOA代谢5-羟色胺和其他单胺，人类群体具有相似的低活性和高活性多态分布。这项研究的发现，结合临床研究和经验，可以帮助指导儿童安全使用氟西汀。

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.