Long Nathan, Long Bertha, Mana Asma, Le Dream, Nguyen Lam, Chokr Sima, Sinchak Kevin
Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States.
Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States.
Horm Behav. 2017 Mar;89:98-103. doi: 10.1016/j.yhbeh.2016.12.013. Epub 2017 Jan 4.
In the female rat, sexual receptivity (lordosis) can be facilitated by sequential activation of estrogen receptor (ER) α and G protein-coupled estrogen receptor 1 (GPER) by estradiol. In the estradiol benzoate (EB) primed ovariectomized (OVX) rat, EB initially binds to ERα in the plasma membrane that complexes with and transactivates metabotropic glutamate receptor 1a to activate β-endorphin neurons in the arcuate nucleus of the hypothalamus (ARH) that project to the medial preoptic nucleus (MPN). This activates MPN μ-opioid receptors (MOP), inhibiting lordosis. Infusion of non-esterified 17β-estradiol into the ARH rapidly reduces MPN MOP activation and facilitates lordosis via GPER. Tamoxifen (TAM) and ICI 182,780 (ICI) are selective estrogen receptor modulators that activate GPER. Therefore, we tested the hypothesis that TAM and ICI rapidly facilitate lordosis via activation of GPER in the ARH. Our first experiment demonstrated that injection of TAM intraperitoneal, or ICI into the lateral ventricle, deactivated MPN MOP and facilitated lordosis in EB-primed rats. We then tested whether TAM and ICI were acting rapidly through a GPER dependent pathway in the ARH. In EB-primed rats, ARH infusion of either TAM or ICI facilitated lordosis and reduced MPN MOP activation within 30min compared to controls. These effects were blocked by pretreatment with the GPER antagonist, G15. Our findings demonstrate that TAM and ICI deactivate MPN MOP and facilitate lordosis in a GPER dependent manner. Thus, TAM and ICI may activate GPER in the CNS to produce estrogenic actions in neural circuits that modulate physiology and behavior.
在雌性大鼠中，雌二醇对雌激素受体（ER）α和G蛋白偶联雌激素受体1（GPER）的顺序激活可促进性接受能力（脊柱前凸）。在经苯甲酸雌二醇（EB）预处理的去卵巢（OVX）大鼠中，EB最初与质膜中的ERα结合，该复合物与促代谢型谷氨酸受体1a结合并使其反式激活，从而激活下丘脑弓状核（ARH）中投射到内侧视前核（MPN）的β-内啡肽神经元。这会激活MPN中的μ-阿片受体（MOP），抑制脊柱前凸。向ARH中注入非酯化的17β-雌二醇可迅速降低MPN中MOP的激活，并通过GPER促进脊柱前凸。他莫昔芬（TAM）和ICI 182,780（ICI）是激活GPER的选择性雌激素受体调节剂。因此，我们测试了TAM和ICI通过激活ARH中的GPER迅速促进脊柱前凸的假设。我们的第一个实验表明，腹腔注射TAM或向侧脑室注射ICI可使EB预处理大鼠的MPN MOP失活并促进脊柱前凸。然后，我们测试了TAM和ICI是否通过ARH中依赖GPER的途径快速发挥作用。在EB预处理的大鼠中，与对照组相比，向ARH中注入TAM或ICI可在30分钟内促进脊柱前凸并降低MPN MOP的激活。这些作用被GPER拮抗剂G15预处理所阻断。我们的研究结果表明，TAM和ICI以依赖GPER的方式使MPN MOP失活并促进脊柱前凸。因此，TAM和ICI可能在中枢神经系统中激活GPER，从而在调节生理和行为的神经回路中产生雌激素样作用。
