Progestins non-genomic actions for socio-sexual behavior

孕激素对社会性行为的非基因组作用

• 批准号: 6894803
• 负责人: CHERYL Anne FRYE
• 金额: $ 19.99万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894803
• 关键词: GABA receptor; NMDA receptors; behavior test; behavioral /social science research tag; benzodiazepine receptor; corticosterone; endocrinology; estrogens; estrus; ethology; female; hormone regulation /control mechanism; laboratory rat; ovariectomy; pregnane compound; progesterone; progestins; psychobiology; psychopharmacology; radioimmunoassay; sex behavior; social behavior; steroid biosynthesis; steroid metabolism; tegmentum

DESCRIPTION (provided by applicant): Progestins mediate the onset and duration of the mating posture, lordosis, in female rodents through actions in the hypothalamus and ventral tegmental area (VTA). In the hypothalamus, progesterone (P) has traditional, "genomic" actions via intracellular progestin receptors (PRs). In the VTA, 3a-hydroxy-5a-pregnan-20-one (3a,5a-THP) has "non-genomic" actions independent of PRs to facilitate lordosis that may involve GABA-Benzodiazepine receptors (GBRs) and/or NMDA type glutamate receptors (NMDARs). In addition to lordosis, 3a,5a-THP may influence other social behaviors, as well as exploration and anxiety. Levels of 3a,5a-THP can also change with behavioral and/or environmental stimuli. Thus, experiments will test the hypothesis that rapid biosynthesis of, or metabolism to, 3a,5a-THP and its non-genomic actions at GBRs and/or NMDARs influence social and sexual behaviors (socio-sexual behaviors) and socio-sexual behaviors alter central 3a,5a-THP concentrations via similar mechanisms. Using classic behavioral endocrinology, pharmacology, and radioimmunoassay methods in a model of socio-sexual behaviors, experiments will investigate: 1) the causal effects of 3a,5a-THP in the midbrain VTA to facilitate socio-sexual behaviors. 2) The effects of various socio-sexual behaviors on midbrain 3a,5a-THP levels. If midbrain 3a,5a-THP is altered in response to socio-sexual behaviors, then this will suggest 3a,5a-THP in the midbrain mediates, and can be reflexively altered by, socio-sexual stimuli. 3) 3a,5a-THP can be formed in the VTA from metabolism of progestins produced peripherally by endocrine glands or centrally via biosynthesis in glial cells. The relative importance of 3a,5a-THP in the VTA from central biosynthesis vs metabolism of peripheral progestins to effect, or be increased by, socio-sexual behaviors will be investigated. 4) 3a,5a-THP may have actions at non-genomic substrates, such as GBRs and/or NMDARs. Whether behavioral effects of 3a,5a-THP, or 3a,5a-THP formation in response to socio-sexual behaviors, are in part due to non-genomic actions at these receptors in the VTA will be examined. Together, these experiments will elucidate the function, source, and mechanisms of 3a,5a-THP's actions in the VTA for socio-sexual behaviors and reveal how 3a,5a-THP increases in response to these behaviors. This research, investigating novel behavioral functions of 3a,5a-THP, will extend knowledge of the neurobiology of progestins, relevant for socio-sexual behaviors, and their connections to systems that regulate emotions. 3a,5a-THP is implicated in stress and the pathophysiology and treatment of neuropsychiatric disorders. Thus, 3a,5a-THP's role and actions to enhance reproduction and social bonds, minimize aggression, influence affective aspects of social behaviors, and to mediate responses to behavioral and/or environmental stimuli needs to be understood.

描述（由申请方提供）：孕激素通过下丘脑和腹侧被盖区（VTA）的作用介导雌性啮齿动物交配姿势（脊柱前凸）的开始和持续时间。 在下丘脑中，孕酮（P）通过细胞内孕酮受体（PR）具有传统的“基因组”作用。在VTA中，3 α-羟基-5 α-葡聚糖-20-酮（3 α，5 α-THP）具有不依赖于PR的“非基因组”作用，以促进可能涉及GABA-苯并二氮卓受体（GBR）和/或NMDA型谷氨酸受体（NMDAR）的脊柱前凸。 除了脊柱前凸，3a，5a-THP可能会影响其他社会行为，以及探索和焦虑。 3a，5a-THP的水平也可以随着行为和/或环境刺激而改变。 因此，实验将检验以下假设：3 α，5 α-THP的快速生物合成或代谢及其在GBR和/或NMDAR的非基因组作用影响社会和性行为（社会性行为），并且社会性行为通过类似的机制改变中枢3 α，5 α-THP浓度。 在社会性行为模型中使用经典的行为内分泌学、药理学和放射免疫测定方法，实验将研究：1）中脑VTA中3a，5a-THP促进社会性行为的因果作用。 2)不同社会性行为对中脑3a，5a-THP水平的影响 如果中脑3a，5a-THP响应于社会性行为而改变，那么这将表明中脑中的3a，5a-THP介导，并且可以被社会性刺激反射性地改变。 3)3 α，5 α-THP可以在VTA中由内分泌腺外周产生的孕激素代谢形成，或通过神经胶质细胞中的生物合成在中枢形成。 将研究3a，5a-THP在VTA中从中枢生物合成与外周孕激素代谢影响社会性行为或被社会性行为增加的相对重要性。 4)3a，5a-THP可能对非基因组底物，如GBR和/或NMDAR具有作用。 将检查响应于社会性行为的3a，5a-THP或3a，5a-THP形成的行为效应是否部分归因于VTA中这些受体的非基因组作用。 总之，这些实验将阐明3a，5a-THP在VTA中对社会性行为的作用的功能、来源和机制，并揭示3a，5a-THP如何响应这些行为而增加。 这项研究调查了3a，5a-THP的新行为功能，将扩展孕激素的神经生物学知识，与社会性行为相关，以及它们与调节情绪的系统的联系。 3 α，5 α-THP与应激和神经精神障碍的病理生理学和治疗有关。 因此，3a，5a-THP的作用和行动，以提高生殖和社会债券，最大限度地减少侵略，影响社会行为的情感方面，并调解行为和/或环境刺激的反应需要理解。