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: 8269119
• 负责人: CHERYL Anne FRYE
• 金额: $ 31.87万
• 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 2013-01-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269119
• 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; RNA; 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）：孕激素（P）部分通过其产物3 α-羟基-5 α-葡聚糖-20-酮（3 α，5 α-THP）的作用介导雌性啮齿动物的探索、焦虑、社会反应。在腹侧被盖区（VTA）中，3 α，5 α-THP通过GABAA/苯并二氮卓（GBR）和/或NMDA型谷氨酸（NMDAR）而不是通过细胞内β-胡萝卜素受体具有促进情感和社会行为的作用。中脑腹侧被盖区中的3a，5a-THP水平既促进情感和社交行为，又因情感和社交行为而增强。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，PXR依赖的生物合成的3a，5a-THP在腹侧被盖区的基础上促进，和/或响应，情感和社会行为。使用行为内分泌学、药理学的经典方法，结合分子生物学的工具，在大鼠情感/社会行为模型中，将研究以下目标。1)PXR在中脑VTA中对3a，5a-THP促进情感/社会行为的因果作用2)情感/社会行为对PXR依赖的中脑3a，5a-THP水平的影响如果PXR和3 α，5 α-THP响应于情感/社会行为而改变，并且阻断PXR减弱了行为诱导的3 α，5 α-THP，则中脑中3 α，5 α-THP介导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可以通过卵巢或肾上腺外周产生的P代谢或通过大脑生物合成集中产生的P代谢在腹侧被盖中形成。将研究PXR对3 α，5 α-THP在VTA中的作用，所述VTA由中枢生物合成和/或外周P的代谢产生，以促进情感/社会行为或由情感/社会行为增加。4)图3a、5a-THP可以具有涉及GBR和/或NMDAR的PXR依赖性动作。将检查响应于情感/社会行为的3 α，5 α-THP或3 α，5 α-THP形成的行为效应是否部分归因于GBR和/或NMDAR处的PXR依赖性效应。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知识，与情感/社会行为相关，以及它们与调节情绪的系统的联系。3 α，5 α-THP涉及神经精神障碍的应激调节、病理生理学和/或治疗。因此，进一步了解3a，5a-THP的作用和机制，以提高生殖/社会债券，尽量减少侵略，影响社会行为的情感方面，并调解对压力的反应，是必不可少的。 公共卫生相关性：孕激素介导啮齿动物的探索，焦虑和社会反应行为，部分通过中脑腹侧被盖区（VTA）的非经典动作，并可以通过参与情感和社会行为来增强。本研究将探讨中脑腹侧被盖区中异生素受体（PXR）介导孕激素形成的作用及其非传统作用。阐明PXR作为这种现象的介导因素，将提供更好的了解孕激素的机制，潜在的性别和/或生殖介导的影响，社会和/或情感过程，和/或病因和/或治疗的一些应激敏感性神经精神障碍。进一步了解孕激素的作用和机制是至关重要的，提供洞察规范和病理生理过程。