Steroid Regulation of Serotonin in Males

男性血清素的类固醇调节

• 批准号: 8079556
• 负责人: CYNTHIA Louise BETHEA
• 金额: $ 33.46万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079556
• 关键词: Aggressive behavior; Agonist; Androgen Receptor; Androgens; Anger; Animals; Anxiety Disorders; Aromatase; Aromatase Inhibitors; Behavior; Control Animal; Disease; Dorsal; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Equilibrium; Estrogen Receptor beta; Estrogen Receptors; Female; Fenfluramine; Fiber; Functional disorder; Gene Expression; Genes; Genetic Polymorphism; Glycols; Goals; Grant; High Pressure Liquid Chromatography; Hostility; Human; Impulsive Behavior; Impulsivity; In Situ Hybridization; Individual; Japanese Population; Knowledge; Lead; Ligands; Macaca; Macaca mulatta; Measures; Mediating; Mental Depression; Metabolic; Molecular; Monoamine Oxidase A; Monoamine Oxidase B; Mus; Neurons; Neurophysiology - biologic function; Norepinephrine; Nuclear; Oxidoreductase; Pathology; Perception; Placebos; Play; Population; Primates; Prolactin; Psychopathology; Rage; Rattus; Regulation; Rodent; Role; Serotonin; Serotonin Production; Steroid Receptors; Steroids; Stimulus; System; TDO2 gene; Testing; Testosterone; Violence; Woman; behavior observation; density; experience; human male; immunocytochemistry; inhibitor/antagonist; locus ceruleus structure; male; men; men' s group; monoamine; nerve supply; neurotransmission; nonhuman primate; noradrenergic; novel; public health relevance; raphe nuclei; receptor; relating to nervous system; research study; social; stressor

DESCRIPTION (provided by applicant): The serotonin system governs many higher order neural functions that control the interaction and perception of an individual with their internal and external environment. As such, dysfunction of the serotonin system has been implicated in a wide variety of psychopathologies. Deficits in serotonin appear to precipitate depression and anxiety disorders more frequently in women, but deficits in serotonin in men often underlie irritability, hostility, anger, rage, and aggression leading to violence. Psychologically this has been attributed to women turning anger inward, versus men turning anger outward due to social rearing experience. This notion is unsatisfying on a molecular level and it does not integrate knowledge of androgens and aggression in animals. Since 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 (ER¿) and androgen receptors (AR) and that the balance of activity at these receptors governs serotonin synthesis and neural function, which in turn, controls aggression. To test this hypothesis, 5 aims are proposed. Aims 1 and 2 will establish groups of male macaques and manipulate the activity of ER2 and AR with enzyme inhibitors and a selective ER¿ agonist, 8BV-E¿ from Bayer-Schering. Behavior and global serotonin will be assessed. Aims 3, 4 and 5 will determine whether ER¿, 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. Serotonin fiber density will be measured in the locus coeruleus with immunocytochemistry and stereology for an indication of serotonin neurotransmission, and to obtain preliminary support for the potential involvement of norepinephrine. Together, these experiments will further our understanding of the regulation of the serotonin system in male primates. PUBLIC HEALTH RELEVANCE: Androgens increase aggression and violent, impulsive behavior and the serotonin system regulates these behaviors. The goal of this grant is to determine how androgens regulate the serotonin neural system in male nonhuman primates. A regulatory mechanism is proposed that could lead to a novel treatment in psychiatric illnesses with explosive rage and impulse disorders.

描述（由适用提供）：5-羟色胺系统控制着许多高阶中性功能，这些功能控制一个人与内部和外部环境的相互作用和感知。因此，血清素系统的功能障碍已在多种心理病理学中实施。羟色胺的缺陷似乎更频繁地抑郁症和焦虑症，但在男性中定义了5-羟色胺的烦恼，敌意，愤怒，愤怒和侵略性的基础，导致暴力。从心理上讲，这归因于妇女向内愤怒，而男性由于社会抚养经历而向外愤怒。这个概念在分子水平上不满意，并且不整合对动物的雄激素和侵略性的知识。由于5-羟色胺系统介导了冲动的行为和侵略性，因此已经有理由将雄激素作用于5-羟色胺系统以减少5-羟色胺的作用，从而增加冲动性。然而，缺乏男性和非人类灵长类动物的5-羟色胺神经元中类固醇受体谱的知识，并且对雄激素对5-羟色胺神经元中基因表达的作用知之甚少。我们假设雄性灵长类动物中的5-羟色胺神经元表达雌激素受体β（ER¿）和雄激素受体（AR），并且这些受体的活性平衡控制着血清素的合成和神经功能，而神经功能又控制着侵略性。为了检验这一假设，提出了5个目标。目标1和2将建立一组雄性猕猴，并用酶抑制剂和AR2和AR的活性来操纵来自拜耳（Bayer-Schering）的酶抑制剂和选择性的ER？Agonist，8BV-E。将评估行为和全球5-羟色胺。 AIM 3、4和5将确定ER¿，AR和关键代谢酶是否位于血清素神经元中，以及它们是否受睾丸激素代谢物调节。此外，将通过原位杂交确定血清素相关基因TPH2，SERT，5HT1A，MAO-A和MAO-B的调节。 5-羟色胺纤维密度将在局部凝血酶中测量，并具有免疫细胞化学和立体学，以表明血清素神经传递，并获得对去甲肾上腺素潜在参与的初步支持。这些实验将共同进一步了解男性私人中5-羟色胺系统的调节。 公共卫生相关性：雄激素会增加侵略性和暴力，冲动行为，血清素系统调节这些行为。这笔赠款的目的是确定雄激素如何在男性非人类隐私中调节血清素神经元系统。提出了一种调节机制，该机制可能导致在具有爆炸性愤怒和冲动疾病的精神病中进行新的治疗方法。