OVARIAN STEROID REGULATION OF SEROTONIN NEURAL FUNCTION

卵巢类固醇对血清素神经功能的调节

• 批准号: 8357840
• 负责人: CYNTHIA Louise BETHEA
• 金额: $ 5.82万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357840
• 关键词: Aggressive behavior; Androgen Receptor; Androgens; Aromatase Inhibitors; Behavior; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Equilibrium; Estrogen Receptor beta; Estrogens; Fenfluramine; Funding; Gene Expression; Genes; GlaxoSmithKline brand of dutasteride; Grant; Impulsive Behavior; Impulsivity; In Situ Hybridization; Japanese Population; Knowledge; Letrozole; Macaca; Mediating; Metabolic; Monitor; Monoamine Oxidase A; Monoamine Oxidase B; National Center for Research Resources; Neurons; Neurophysiology - biologic function; Ovarian; Oxidoreductase; Placebos; Primates; Principal Investigator; Regulation; Research; Research Infrastructure; Resources; Schedule; Serotonin; Serum; Source; Stanolone; Steroid Receptors; Steroids; System; TDO2 gene; Testosterone; Treatment Efficacy; United States National Institutes of Health; cost; human male; inhibitor/antagonist; male; men' s group; nonhuman primate; receptor; relating to nervous system

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a new project/grant examining the action of androgens on behavior and gene expression in the serotonin neural system. The serotonin system mediates impulsive behavior and aggression. It has been reasoned that androgens act on the serotonin system to reduce serotonin and thereby increase impulsivity. However, knowledge of the steroid receptor profile in serotonin neurons of male human and nonhuman primates is lacking and little is known of the actions of androgens on gene expression in serotonin neurons. We hypothesize that serotonin neurons in male primates express estrogen receptor beta (ERb) and androgen receptors (AR) and that the balance of activity at these receptors governs serotonin synthesis and neural function, which in turn, controls aggression. We will establish groups of male macaques and manipulate the activity of ERb and AR with enzyme inhibitors. Behavior and global serotonin will be assessed.We will determine whether ERb, AR, and pivotal metabolic enzymes are localized in serotonin neurons and whether they are regulated by testosterone metabolites. In addition, the regulation of serotonin-related genes TPH2, SERT, 5HT1A, MAO-A and MAO-B will be determined with in situ hybridization. Male Japanese macaques have been castrated and are currently in treatment with placebo, testosterone (T), T+ Letrozole (aromatase inhibitor) and T+Avodart (5a reductase inhibitor)(n=5/group). Serum levels of estrogen, testosterone and dihydrotestosterone are being monitored to verify the efficacy of treatment. Fenfluramine challenges to determine the global availability of serotonin are scheduled in two weeks.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这是一个新的项目/赠款检查雄激素对行为和基因表达在5-羟色胺神经系统的作用。血清素系统调节冲动行为和攻击性。据推测，雄激素作用于血清素系统，减少血清素，从而增加冲动。然而，知识的类固醇受体分布在5-羟色胺神经元的男性人类和非人灵长类动物是缺乏和鲜为人知的行动，雄激素对5-羟色胺神经元的基因表达。我们假设，在雄性灵长类动物中的5-羟色胺神经元表达雌激素受体β（ERb）和雄激素受体（AR），这些受体的活性的平衡支配5-羟色胺的合成和神经功能，这反过来又控制侵略。我们将建立雄性猕猴组，并使用酶抑制剂操纵ERb和AR的活性。我们将评估行为和总体5-羟色胺，并确定ERb、AR和关键代谢酶是否定位于5-羟色胺神经元，以及它们是否受睾酮代谢物的调节。此外，还将用原位杂交技术检测与胡萝卜素相关的基因TPH 2、SERT、5 HT 1A、MAO-A和MAO-B的调控。 雄性日本猕猴已被阉割，目前正在接受安慰剂、睾酮（T）、T+来曲唑（芳香酶抑制剂）和T+Avodart（5 α还原酶抑制剂）治疗（n=5/组）。正在监测雌激素、睾酮和双氢睾酮的血清水平，以验证治疗的疗效。芬氟拉明挑战，以确定全球5-羟色胺的供应定于两周内。