The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents
The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents
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DOI：
10.1016/s0165-0173(01)00119-9
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发表时间：
2001-11-01
影响因子：
--
通讯作者：
Frye, CA
中科院分区：
文献类型：
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作者：
Frye, CA
孕激素和雄激素调节性感受性，部分是通过独立于传统细胞内类固醇受体的机制。下丘脑腹内侧核(VMH)和腹侧被盖(VTA)中的孕酮(PROG)促进前凸，但在这两个脑区的作用不同。主要使用啮齿动物的前凸作为活体实验模型，我们检查了孕激素对中脑和下丘脑的影响。定位和阻滞剂研究表明，Prog在VMH的作用需要细胞内孕激素受体(PR)，而在VTA中则不需要。具有快速膜效应和/或对PR缺乏亲和力的孕激素，在应用于VTA时，有助于前凸。操纵VTA中的GABA和/或GABA(A)/苯二氮卓受体复合体(GBRs)可改变前凸，提示孕激素可能与GBRs相互作用，通过增强GABA能神经元的功能来促进感受性。在VTA内干扰最有效的内源性GBR激动剂3α-羟基-5α-孕激素-20-酮(3α，5α-prog或别孕酮)的代谢或生物合成，可减弱啮齿类动物的雌性性行为，刺激线粒体苯二氮卓类受体(MBR)，通过向VTA注入MBR激动剂来增强神经类固醇的产生，从而增强前凸。3Alpha，5Alpha-TH蛋白在交配的发情前期和发情间期啮齿动物的中脑增加。这些数据表明，在VTA中，PROG可能促进3α，5α-PROG的代谢和/或生物合成后的前凸，这可能在GBR和/或MBR处有后续作用，从而敏锐地调节啮齿类动物的雌性性行为。双氢睾酮(DHT)的3α-羟基类固醇氧化还原代谢物5α-雄烷-3α，17β-二醇(3α-雄烷二醇)对终止啮齿动物的性感受性是重要的，并且在细胞内没有功能性雄激素受体的情况下具有这些作用。此外，改变下丘脑的GBR功能可以影响3Alpha-雄烯二醇对性接受能力的抑制。通过下丘脑中不依赖于细胞内雄激素受体但涉及GBRs的作用，3α-雄烯二醇抑制前凸。这些发现表明，孕激素代谢物和孕烷神经类固醇3α，5α-前列腺素，以及睾酮代谢物和雄烯类神经类固醇3α-雄烯二醇，可以通过细胞内类固醇受体的非经典作用对前凸产生直接影响。(C)2001 Elsevier Science B.V.保留所有权利。
Progestins and androgens modulate sexual receptivity in rodents, in part through mechanisms independent of traditional intracellular steroid receptors. Progesterone (PROG) in the ventromedial hypothalamus (VMH) and ventral tegmental (VTA) facilitates lordosis but has different actions in these brain areas. Primarily using lordosis in rodents as an in vivo experimental model, we have examined the effects that progestins exert in the midbrain and hypothalamus. Localization and blocker studies indicate that PROG's actions in the VMH require intracellular progestin receptors (PRs) but in the VTA they do not. Progestins that have rapid, membrane effects, and/or are devoid of affinity for PRs, facilitate lordosis when applied to the VTA. Manipulation of GABA and/or GABA(A)/benzodiazepine receptor complexes (GBRs) in the VTA alters lordosis, which suggests that progestins may interact with GBRs to facilitate receptivity by enhancing the function of GABAergic neurons. Interfering with PROG's metabolism to, or the biosynthesis of, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG or allopregnanolone), the most effective endogenous GBR agonist, in the VTA attenuates female sexual behavior in rodents, Stimulation of mitochondrial benzodiazepine receptors (MBRs), which enhances neurosteroid production, by infusions of an MBR agonist to the VTA enhances lordosis. 3alpha,5alpha-TH PROG is increased in the midbrain of mated>proestrous>diestrous rodents. These data suggest that in the VTA, PROG may facilitate lordosis following metabolism to and/or biosynthesis of 3alpha,5alpha-TH PROG, which may have subsequent actions at GBRs and/or MBRs to acutely modulate female sexual behavior in rodents. The 3alpha-hydroxysteroid oxidoreduced metabolite of dihydrotestosterone (DHT), 5alpha-androstane-3alpha,17beta-diol (3alpha-androstanediol), is important for termination of sexual receptivity in rodents and has these effects in the absence of functional intracellular androgens receptors. As well, altering GBR function in the hypothalamus can influence 3alpha-androstanediol's inhibition of sexual receptivity. Through actions in the hypothalamus that are independent of intracellular androgen receptors but involving GBRs, 3alpha-androstanediol inhibits lordosis. These findings suggest that the PROG metabolite and pregnane neurosteroid, 3alpha,5alpha-TH PROG, and the testosterone metabolite and androstane neurosteroid, 3alpha-androstanediol, can have proximate influences on lordosis that is via nonclassical actions at intracellular steroid receptors. (C) 2001 Elsevier Science B.V. All rights reserved.