Frye C A, Koonce C J, Walf A A
Department of Psychology, The University at Albany-SUNY, Life Sciences 01058, 1400 Washington Ave., Albany, NY, 12222, USA,
Psychopharmacology (Berl). 2014 Sep;231(17):3365-74. doi: 10.1007/s00213-013-3406-0. Epub 2014 Jan 17.
Progesterone and its metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), have actions in the ventral tegmental area (VTA) that are required for lordosis, a characteristic mating posture of female rodents. 17β-estradiol (estradiol) co-varies with progestogens over natural cycles, enhances production of 3α,5α-THP, and is required for successful reproductive behavior.
A question of interest is the role of pregnane xenobiotic receptor (PXR), a nuclear receptor that regulates enzymes needed for the production of 3α,5α-THP, for estradiol-mediated lordosis. The hypothesis tested was that if PXR is involved in estradiol-mediated biosynthesis of 3α,5α-THP and reproductive behavior, knocking down expression of PXR in the VTA of estradiol-primed, but not vehicle-primed, rats should decrease lordosis and midbrain 3α,5α-THP; effects may be attenuated by 3α,5α-THP administered to the VTA.
Ovariectomized rats were administered subcutaneous injections of oil vehicle or estradiol. Rats were then administered PXR antisense oligonucleotides (PXR AS-ODNs; which are expected to locally knock down expression of PXR), or control (saline), infusions to the VTA. Rats were administered 3α,5α-THP or vehicle via infusions to the VTA. Reproductive behavior (paced mating task) of rats was determined in addition to exploratory (open field), affective (elevated plus maze), and pro-social (social interaction task) behavior.
Reproductive behavior (i.e., increased lordosis) was enhanced with estradiol-priming and infusions of 3α,5α-THP to the VTA. Infusions of PXR AS-ODNs to the VTA attenuated responses in estradiol-, but not vehicle-, primed rats, compared to control infusions.
PXR may be involved in a neuroregulatory response involving biosynthesis of 3α,5α-THP in the midbrain VTA of estradiol-primed rats.
孕酮及其代谢产物5α-孕烷-3α-醇-20-酮（3α,5α-四氢孕酮）在腹侧被盖区（VTA）发挥作用，而这种作用是雌性啮齿动物特征性交配姿势——脊柱前凸所必需的。在自然周期中，17β-雌二醇（雌二醇）与孕激素共同变化，可增强3α,5α-四氢孕酮的生成，并且是成功进行生殖行为所必需的。
一个有趣的问题是孕烷异生素受体（PXR）在雌二醇介导的脊柱前凸中的作用，PXR是一种核受体，可调节3α,5α-四氢孕酮生成所需的酶。所检验的假设是，如果PXR参与雌二醇介导的3α,5α-四氢孕酮生物合成和生殖行为，那么在经雌二醇预处理而非经赋形剂预处理的大鼠的VTA中敲低PXR的表达，应该会降低脊柱前凸和中脑3α,5α-四氢孕酮水平；向VTA注射3α,5α-四氢孕酮可能会减弱这些效应。
对去卵巢大鼠皮下注射油赋形剂或雌二醇。然后，对大鼠向VTA注射PXR反义寡核苷酸（PXR AS-ODNs，预期可在局部敲低PXR的表达）或对照（生理盐水）。通过向VTA注射，给大鼠施用3α,5α-四氢孕酮或赋形剂。除了探索行为（旷场试验）、情感行为（高架十字迷宫试验）和亲社会行为（社会互动试验）外，还测定了大鼠的生殖行为（定速交配任务）。
经雌二醇预处理并向VTA注射3α,5α-四氢孕酮可增强生殖行为（即增加脊柱前凸）。与对照注射相比，向VTA注射PXR AS-ODNs减弱了经雌二醇预处理而非经赋形剂预处理大鼠的反应。
PXR可能参与了一种神经调节反应，该反应涉及经雌二醇预处理大鼠中脑VTA中3α,5α-四氢孕酮的生物合成。
