Progestogens' non-classical effects and mechanisms for social & mood processes

孕激素对社会的非经典效应和机制

• 批准号: 7787894
• 负责人: CHERYL Anne FRYE
• 金额: $ 32.19万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787894
• 关键词: Adrenal Cortex Hormones; Adrenal Glands; Affective; Aggressive behavior; Agonist; Anabolism; Antisense Oligodeoxyribonucleotides; Anxiety; Area; Attenuated; Behavior; Behavioral; Benzodiazepine Receptor; Benzodiazepines; Biological Markers; Brain; Corpus striatum structure; Cytochrome P450; Data; Disease; Emotions; Endocrinology; Enzymes; Estradiol; Etiology; Excitatory Amino Acid Antagonists; Female; Functional disorder; Gender; Genetic Transcription; Glutamate Receptor; Glutamates; Gonadal Steroid Hormones; Hippocampus (Brain); Hormonal; Hormones; Infusion procedures; Knowledge; Left; Lordosis; Measures; Mediating; Mental Depression; Mental Health; Metabolism; Methods; Midbrain structure; Modeling; Molecular Biology; Mood Disorders; Moods; N-Methylaspartate; Neurobiology; Neurosecretory Systems; Nuclear Receptors; Oligodeoxyribonucleotides; Ovarian; Ovary; Partner in relationship; Peripheral; Pharmacology; Plasma; Play; Pregnanes; Process; Production; Progesterone; Progesterone Receptors; Progestins; Proteins; Rattus; Receptor Gene; Regulation; Reporting; Reproduction; Research; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Rodent Model; Role; Sex Behavior; Site; Social Behavior; Social Interaction; Steroids; Stimulus; Stress; System; Ventral Tegmental Area; Western Blotting; Woman; Xenobiotics; experience; insight; knock-down; male; men; neuropsychiatry; neurosteroids; novel; outcome forecast; pregnane X receptor; pregnane-20-one; public health relevance; receptor; response; sex; social; social attachment; tool

DESCRIPTION (provided by applicant): Progesterone (P) mediates exploration, anxiety, social responding of female rodents in part through actions of its product, 3a-hydroxy-5a-pregnan-20-one (3a,5a-THP). In the ventral tegmental area (VTA), 3a,5a-THP has actions to facilitate affective and social behaviors through GABAA/Benzodiazepine (GBRs) and/or NMDA type glutamate (NMDARs), rather than via intracellular progestin receptors. 3a,5a-THP levels in the midbrain VTA both facilitate, and are enhanced by, affective and social behavior. The pregnane X receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. Our hypothesis is that PXR-dependent biosynthesis of 3a,5a-THP in the VTA underlies facilitation of, and/or response to, affective and social behavior. Using classic methods of behavioral endocrinology, pharmacology, in conjunction with tools of molecular biology, in a rat model of affective/social behaviors, the following aims will be to investigate. 1) The causal actions of PXR in the midbrain VTA for 3a,5a-THP to facilitate affective/social behaviors. 2) The effects of affective/social behaviors on PXR-dependent midbrain 3a,5a-THP levels. If PXR and 3a,5a-THP are altered in response to affective/social behaviors, and blocking PXR attenuates behavior- induced 3a,5a-THP, then effects of 3a,5a-THP in the midbrain to mediate, and be dynamically altered by, social stimuli are PXR-dependent. 3) 3a,5a-THP can be formed in the VTA from metabolism of P produced peripherally by ovaries or adrenals or centrally via biosynthesis in brain. The role of PXR for 3a,5a-THP in the VTA to be produced from central biosynthesis and/or metabolism from peripheral P to facilitate, or be increased by, affective/social behaviors will be investigated. 4) 3a,5a-THP may have PXR-dependent actions involving GBRs and/or NMDARs. Whether behavioral effects of 3a,5a-THP, or 3a,5a-THP formation in response to affective/social behaviors, are in part due to PXR- dependent effects at GBRs and/or NMDARs, will be examined. Investigating novel behavioral functions of 3a,5a-THP will extend our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate emotions. 3a,5a-THP is implicated in stress regulation, pathophysiology and/or treatment of neuropsychiatric disorders. Thus, further understanding of 3a,5a-THP's role and mechanisms to enhance reproduction/social bonds, minimize aggression, influence affective aspects of social behaviors, and to mediate responses to stress, are essential. PUBLIC HEALTH RELEVANCE: Progestogens mediate exploration, anxiety, and social responding behavior in rodents, in part through non-classic actions in the midbrain ventral tegmental area (VTA), and can be enhanced by engaging in affective and social behaviors. The role of the pregnane xenobiotic receptor (PXR) in mediating formation of progestogens and their non- traditional actions in the midbrain VTA will be investigated. Elucidation of PXR as a mediating factor in this phenomena will provide greater understanding of the mechanisms of progestogens underlying sex and/or hormonally-mediated effects on social and/or affective processes, and/or the etiology and/or treatment of some stress-sensitive neuropsychiatric disorders. Further understanding of progestogens' effects and mechanisms are vital to provide insight into normative and pathophysiological processes.

描述（由申请人提供）：黄体酮 (P) 部分通过其产品 3a-羟基-5a-怀孕-20-酮 (3a,5a-THP) 的作用介导雌性啮齿类动物的探索、焦虑和社交反应。在腹侧被盖区 (VTA)，3a,5a-THP 通过 GABAA/苯二氮卓类 (GBR) 和/或 NMDA 型谷氨酸 (NMDAR)，而不是通过细胞内孕激素受体，促进情感和社会行为。中脑 VTA 中的 3a,5a-THP 水平既促进情感和社会行为，又因情感和社会行为而增强。孕烷 X 受体 (PXR) 介导各种神经生物学因子的产生和/或代谢。 PXR 定位于大鼠的中脑 VTA。我们的假设是，VTA 中 PXR 依赖性的 3a,5a-THP 生物合成是情感和社会行为的促进和/或反应的基础。使用行为内分泌学、药理学的经典方法，结合分子生物学工具，在情感/社会行为的大鼠模型中，将进行以下研究。 1) PXR 在中脑 VTA 中对 3a,5a-THP 的因果作用促进情感/社会行为。 2) 情感/社会行为对 PXR 依赖性中脑 3a,5a-THP 水平的影响。如果 PXR 和 3a,5a-THP 因情感/社会行为而改变，并且阻断 PXR 会减弱行为诱导的 3a,5a-THP，则 3a,5a-THP 在中脑中调节社会刺激并被社会刺激动态改变的作用是 PXR 依赖性的。 3) 3a,5a-THP 可以在 VTA 中由卵巢或肾上腺外周产生的 P 代谢形成，或者通过大脑中的生物合成集中产生。将研究 PXR 对 VTA 中 3a,5a-THP 的作用，该作用是由中枢生物合成和/或外周 P 代谢产生的，以促进情感/社会行为或通过情感/社会行为而增加。 4) 3a,5a-THP 可能具有涉及 GBR 和/或 NMDAR 的 PXR 依赖性作用。将检查 3a,5a-THP 或 3a,5a-THP 形成对情感/社会行为的行为影响是否部分归因于 GBR 和/或 NMDAR 的 PXR 依赖性影响。研究 3a,5a-THP 的新行为功能将扩展我们对孕激素神经生物学的了解，与情感/社会行为相关，以及它们与调节情绪的系统的联系。 3a,5a-THP 涉及应激调节、病理生理学和/或神经精神疾病的治疗。因此，进一步了解 3a,5a-THP 的作用和机制对于增强生殖/社会联系、最大限度地减少攻击性、影响社会行为的情感方面以及调节对压力的反应至关重要。 公共健康相关性：孕激素在啮齿动物中介导探索、焦虑和社会反应行为，部分是通过中脑腹侧被盖区 (VTA) 的非经典行为，并且可以通过参与情感和社会行为来增强。将研究孕烷异生物质受体 (PXR) 在介导孕激素形成中的作用及其在中脑 VTA 中的非传统作用。阐明 PXR 作为这一现象的中介因素，将有助于更好地理解孕激素对社会和/或情感过程的性和/或激素介导作用的机制，和/或某些应激敏感神经精神疾病的病因和/或治疗。进一步了解孕激素的作用和机制对于深入了解规范和病理生理过程至关重要。