Steroid Regulation of Serotonin in Males

描述（由申请人提供）：5-羟色胺系统支配许多高阶神经功能，这些功能控制个体与其内部和外部环境的相互作用和感知。因此，5-羟色胺系统的功能障碍与多种精神病理学有关。5-羟色胺缺乏似乎更容易导致女性抑郁症和焦虑症，但5-羟色胺缺乏通常是男性易怒、敌意、愤怒、暴怒和侵略性的基础，从而导致暴力。从心理学上讲，这是由于女性将愤怒转向内部，而男性则由于社会抚养经验而将愤怒转向外部。这个概念在分子水平上是不令人满意的，它没有整合雄激素和动物攻击性的知识。由于5-羟色胺系统介导冲动行为和攻击性，因此有理由认为雄激素作用于5-羟色胺系统以减少5-羟色胺，从而增加冲动性。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，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 <$）和雄激素受体（AR），这些受体的活性平衡控制5-羟色胺合成和神经功能，这反过来又控制了攻击性。为了验证这一假设，提出了5个目标。目的1和2将建立雄性猕猴群，并使用酶抑制剂和选择性ER <$激动剂（来自Bayer-Schering的8BV-E <$）操纵ER 2和AR的活性。将评估行为和总体血清素。目的3、4和5将确定ER、AR和关键代谢酶是否位于5-羟色胺神经元中，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。将采用免疫细胞化学和体视学测量蓝斑中的5-羟色胺纤维密度，以指示5-羟色胺神经传递，并获得去甲肾上腺素潜在参与的初步支持。总之，这些实验将进一步加深我们对雄性灵长类动物血清素系统调节的理解。 公共卫生相关性：雄激素增加攻击性和暴力，冲动行为和血清素系统调节这些行为。这项资助的目的是确定雄激素如何调节雄性非人类灵长类动物的血清素神经系统。提出了一种调节机制，可能导致一种新的治疗精神疾病的爆炸性愤怒和冲动障碍。

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.