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-孕酮-20-酮(3a，5a-THP)的作用调节雌性啮齿动物的探索、焦虑和社会反应。在腹侧被盖区，3a，5a-THP通过GABAA/苯二氮(GBRs)和/或NMDA型谷氨酸(NMDARs)促进情感和社会行为，而不是通过细胞内孕激素受体。中脑VTA中的3a，5a-THP水平既促进了情感行为和社交行为，也受到了这种行为的增强。孕烷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，VTA中依赖PXR的3a，5a-THP的生物合成是促进和/或对情感和社会行为的反应的基础。利用行为内分泌学、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，将进行以下目的的研究。1)PXR在中脑VTA的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3a，5a-THP因情感/社会行为而改变，并且阻断PXR可以减弱行为诱导的3a，5a-THP，那么3a，5a-THP在中脑对社会刺激的调节和动态改变的作用是依赖于PXR的。3)3a、5a-THP可由卵巢、肾上腺外周产生的P或中枢脑内生物合成的P在VTA内形成。3a，5a-THP的PXR在中枢生物合成和/或外周P代谢产生的VTA中的作用将被研究，以促进或增加情感/社会行为。4)3a，5a-THP可能具有依赖PXR的作用，涉及GBR和/或NMDAR。将研究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依赖效应。研究3a，5a-THP的新的行为功能将扩大我们对与情感/社会行为相关的孕激素的神经生物学的了解，以及它们与调节情绪的系统的联系。3a，5a-THP参与应激调节、病理生理学和/或神经精神障碍的治疗。因此，进一步了解3a，5a-THP在增强生殖/社会纽带、减少攻击性、影响社会行为的情感方面以及调节应激反应方面的作用和机制是至关重要的。 与公共健康相关：孕激素调节啮齿动物的探索、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，并可以通过参与情感和社会行为来增强。孕烷异源受体(PXR)在调节孕激素形成中的作用及其在中脑VTA中的非传统作用将被研究。阐明PXR作为这一现象的中介因子将有助于更好地理解孕激素在社会和/或情感过程中的性别和/或激素中介作用的机制，和/或某些应激敏感型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洞察正常和病理生理过程至关重要。

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.