OVARIAN STEROID REGULATION OF SEROTONIN NEURAL FUNCTION

卵巢类固醇对血清素神经功能的调节

基本信息

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
项目类别：
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&apos s group nonhuman primate receptor relating to nervous system

项目摘要

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.

该子项目是利用资源的众多研究子项目之一由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持并且子项目的首席研究员可能是由其他来源提供的，包括其他 NIH 来源。子项目可能列出的总成本代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。这是一个新项目/资助，研究雄激素对血清素神经系统行为和基因表达的作用。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，对雄性人类和非人类灵长类动物血清素神经元中类固醇受体谱的了解尚缺乏，并且雄激素对血清素神经元基因表达的作用知之甚少。我们假设雄性灵长类动物的血清素神经元表达雌激素受体β（ERb）和雄激素受体（AR），并且这些受体的活性平衡控制着血清素合成和神经功能，进而控制攻击性。我们将建立雄性猕猴群体并用酶抑制剂操纵 ERb 和 AR 的活性。我们将评估行为和整体血清素。我们将确定 ERb、AR 和关键代谢酶是否位于血清素神经元中，以及它们是否受到睾酮代谢物的调节。此外，血清素相关基因TPH2、SERT、5HT1A、MAO-A和MAO-B的调节将通过原位杂交来确定。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（5a 还原酶抑制剂）治疗（n=5/组）。正在监测雌激素、睾酮和二氢睾酮的血清水平，以验证治疗效果。确定全球血清素供应情况的芬氟拉明挑战计划将在两周内进行。