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: 7627418
• 负责人: CHERYL Anne FRYE
• 金额: $ 5.87万
• 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 2009-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627418
• 关键词: Adrenal Glands; Affective; Affinity; Aggressive behavior; Agonist; Anabolism; Animal Model; Anxiety; Attenuated; Behavior; Behavioral; Benzodiazepine Receptor; Binding; Brain; Complex; Corticosterone; D Aspartate; Data; Diestrus; Disease; Emotions; Endocrine Glands; Endocrinology; Enzymes; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Functional disorder; Genomics; Glutamate Receptor; Hydroxysteroids; Hypothalamic structure; Incidence; Individual; Infusion procedures; Knowledge; Lordosis; Mediating; Metabolism; Methods; Midbrain structure; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neurobiology; Neuroglia; Nociception; Ovarian; Oxidoreductase; Partner in relationship; Peripheral; Pharmacology; Posture; Proestrus; Progesterone; Progesterone Receptors; Progestins; Radioimmunoassay; Rattus; Relative (related person); Reproduction; Research; Rodent; Role; Sex Behavior; Social Behavior; Source; Stimulus; Stress; System; Variant; Ventral Tegmental Area; neuropsychiatry; non-genomic; novel; pregnane-20-one; primin; receptor; research study; response; sex; social; social attachment

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(由申请人提供)：孕激素通过下丘脑和腹侧被盖区(VTA)的作用调节雌性啮齿动物交配姿势(前凸)的开始和持续时间。在下丘脑，孕酮(P)通过细胞内孕激素受体(PR)具有传统的“基因组”作用。在VTA中，3a-羟基-5a-孕烷-20-酮(3a，5a-THP)具有独立于PR的促进前凸的“非基因组”作用，可能涉及GABA-苯二氮卓受体(GBRs)和/或NMDA型谷氨酸受体(NMDARs)。除前凸外，3a、5a-THP还可能影响其他社会行为，以及探索和焦虑。3a，5a-THP水平也会随着行为和/或环境刺激而变化。因此，实验将检验这一假设，即3a，5a-THP的快速生物合成或代谢及其在GBR和/或NMDAR处的非基因组作用影响社会和性行为(社会-性行为)，社会-性行为通过类似的机制改变中枢3a，5a-THP浓度。使用经典的行为内分泌学、药理学和放射免疫分析方法，在社会性行为模型中，实验将调查：1)3a，5a-THP在中脑VTA促进社会性行为的因果效应。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随着社会性行为的改变而改变，那么这将表明3a，5a-THP在中脑中起调节作用，并且可以被社会性刺激条件性地改变。3)3a、5a-THP可在VTA内由内分泌腺产生的孕激素代谢而形成，或由神经胶质细胞的生物合成在中央形成。3a，5a-THP在VTA中从中枢生物合成到外周孕激素代谢对社会性行为的影响或被增加的相对重要性将被调查。4)3a，5a-THP可能作用于非基因组底物，如GBR和/或NMDAR。3a，5a-THP或3a，5a-THP的形成对社会性行为的行为影响是否部分归因于VTA中这些受体的非基因组作用，将被研究。总之，这些实验将阐明3a，5a-THP在VTA中对社会性行为的作用、来源和机制，并揭示3a，5a-THP是如何随着这些行为的反应而增加的。这项研究调查了3a，5a-THP的新的行为功能，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。3a，5a-THP与应激以及神经精神疾病的病理生理学和治疗有关。因此，需要了解3a，5a-THP在增强生殖和社会联系、减少攻击性、影响社会行为的情感方面以及调节对行为和/或环境刺激的反应方面的作用和行动。