Catalano Paolo N, Bonaventura María Marta, Silveyra Patricia, Bettler Bernhard, Libertun Carlos, Lux-Lantos Victoria A
Instituto de Biología y Medicina Experimental-CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.
Neuroendocrinology. 2005;82(5-6):294-305. doi: 10.1159/000093128.
gamma-Aminobutyric acid (GABA) has been implicated in the control of hypophyseal functions. We evaluated whether the constitutive loss of functional GABA(B) receptors in GABA(B1) knockout (GABA(B1)(-/-)) mice alters hormonal levels, under basal and stimulated conditions, and reproductive function. The serum hormone levels were measured by radioimmunoassay, the estrous cyclicity was evaluated by vaginal lavages, and the mating behavior was determined by the presence of vaginal plugs. A moderate hyperprolactinemic condition was observed, in which prolactin increase and thyroid-stimulating hormone decrease were similar between genotypes. Basal luteinizing hormone (LH), follicle-stimulating hormone, thyroid-stimulating hormone, and growth hormone levels were similar between genotypes in each sex. Analysis of the gonadotropin axis revealed no differences in puberty onset between female genotypes. In con trast, the estrous cyclicity was significantly disrupted in GABA(B1)(-/-) female mice, showing significantly extended periods in estrus and shortened periods in proestrus. Reproduction was significantly compromised in GABA(B1)(-/-) females, with a significantly lower proportion of mice (37.5%) getting pregnant during the first 30 days of mating as compared with wild-type controls (87.5%). Moreover, only 14% of vaginal plug positive GABA(B1)(-/-) females had successful pregnancies as compared with 75% in the controls. In addition, the postovariectomy LH rise was significantly advanced in GABA(B1)(-/-) mice, while the response to estradiol feedback was similar in both genotypes. In conclusion, our endocrine analysis of GABA(B1)(-/-) mice reveals that GABA(B) receptors are involved in the regulation of basal prolactin titers. Moreover, the hypothalamic-hypophyseal-ovarian axis is seriously disturbed, with alterations in cyclicity, postcastration LH increase, and fertility indexes. The molecular mechanism underlying these hormonal disturbances remains to be addressed.
γ-氨基丁酸（GABA）与垂体功能的调控有关。我们评估了GABA(B1)基因敲除（GABA(B1)(-/-)）小鼠中功能性GABA(B)受体的组成性缺失是否会在基础和刺激条件下改变激素水平以及生殖功能。通过放射免疫分析法测定血清激素水平，通过阴道灌洗评估发情周期，并通过阴道栓的存在确定交配行为。观察到一种中度高催乳素血症状态，其中各基因型之间催乳素升高和促甲状腺激素降低情况相似。各性别中，基础促黄体生成素（LH）、促卵泡生成素、促甲状腺激素和生长激素水平在各基因型之间相似。对促性腺激素轴的分析显示，雌性各基因型之间青春期开始时间无差异。相比之下，GABA(B1)(-/-)雌性小鼠的发情周期明显紊乱，发情期显著延长，动情前期缩短。GABA(B1)(-/-)雌性小鼠的生殖功能明显受损，与野生型对照（87.5%）相比，在交配的前30天内怀孕的小鼠比例显著较低（37.5%）。此外，与对照组的75%相比，只有14%的阴道栓阳性GABA(B1)(-/-)雌性小鼠成功怀孕。另外，GABA(B1)(-/-)小鼠卵巢切除术后LH升高明显提前，而两种基因型对雌二醇反馈的反应相似。总之，我们对GABA(B1)(-/-)小鼠的内分泌分析表明，GABA(B)受体参与基础催乳素水平的调节。此外，下丘脑-垂体-卵巢轴受到严重干扰，表现为周期改变、去势后LH升高以及生育指数变化。这些激素紊乱背后的分子机制仍有待研究。
