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

描述（由申请人提供）：孕酮(P)部分通过其产物3a-羟基-5a-孕-20- 1 （3a,5a-THP）的作用介导雌性啮齿动物的探索、焦虑和社会反应。在腹侧被盖区（VTA）， 3a，5a-THP通过GABAA/苯二氮卓类（GBRs）和/或NMDA型谷氨酸（NMDARs）而不是通过细胞内黄体酮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，又被其增强。妊娠X受体（PXR）介导多种神经生物学因子的产生和/或代谢。PXR定位于大鼠中脑VTA。我们的假设是pxr依赖性VTA中3a，5a-THP的生物合成是促进和/或反应情感和社会行为的基础。使用行为内分泌学、药理学的经典方法，结合分子生物学的工具，在大鼠的情感/社会行为模型中，以下目标将被调查。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依赖性中脑3a，5a-THP水平的影响。如果PXR和3a，5a-THP在情感/社会行为中发生改变，阻断PXR会减弱行为诱导的3a，5a-THP，那么3a，5a-THP在中脑中介导并被社会刺激动态改变的作用是PXR依赖的。3) 3a，5a-THP可在VTA中通过卵巢或肾上腺外周产生的P代谢或通过脑内生物合成而形成。PXR在中枢生物合成和/或外周P代谢产生的VTA中促进或通过情感/社会行为增加3a，5 - thp的作用将被研究。4) 3a，5a-THP可能具有pxr依赖性作用，涉及gbr和/或NMDARs。是否3a，5a-THP的行为影响，或3a，5a-THP的形成对情感/社会行为的反应，部分是由于PXR对gbr和/或NMDARs的依赖作用，将被检查。研究3a，5a-THP的新行为功能将扩展我们对孕激素的神经生物学知识，与情感/社会行为相关，以及它们与调节情绪的系统的联系。3a，5 - thp与应激调节、病理生理和/或神经精神疾病的治疗有关。因此，进一步了解3a，5a-THP在增强繁殖/社会联系，减少攻击，影响社会行为的情感方面以及调节压力反应方面的作用和机制是必不可少的。

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.