National Research Council of Italy (CNR), Institute of Neuroscience, Section of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
Pharmacol Biochem Behav. 2012 Aug;102(2):366-72. doi: 10.1016/j.pbb.2012.05.011. Epub 2012 May 24.
Fluctuations in the concentrations of the neuroactive steroid allopregnanolone are thought to influence γ-amino-butyric acid type A (GABA(A)) receptor gene expression and function. Long-term treatment with ethinyl estradiol (EE) plus levonorgestrel (LNG), two of the most widely used steroids in the hormonal contraceptive pill, decreases allopregnanolone levels in rat cerebral cortex and plasma, alters GABA(A) receptor expression and induces anxiety-like behavior. We evaluated which component of the hormonal contraceptive pill is responsible for the aforementioned changes. Female rats were injected subcutaneously (s.c.) with EE (0.030 mg) or LNG (0.125 mg) once a day for 4 weeks. Compared to the respective vehicle-treated control groups, EE decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 76, 72 and 33%, respectively and hippocampal levels by 52, 56 and 50%, respectively. Likewise, LNG decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 75, 68 and 33%, respectively, and hippocampal levels by 55, 65 and 60%, respectively. Administration of LNG, but not EE, increased the abundance of the γ2 subunit peptide in cerebral cortex and hippocampus by 38 and 59%, respectively. Further, LNG, but not EE, decreased the time spent and the number of entries into the open arms of the elevated plus maze by 56 and 43%, respectively, an index of anxiety-like behavior. These results suggest that alterations in GABA(A) receptor subunit expression and anxiety-like behavior induced by long-term treatment with combined EE/LNG appear to be caused by LNG. Given that both EE and LNG decrease allopregnanolone levels in a similar manner, these results further suggest that changes in allopregnanolone levels are not associated with GABA(A) receptor expression.
神经活性甾体别孕烯醇酮浓度的波动被认为会影响γ-氨基丁酸 A 型（GABA(A)) 受体基因表达和功能。长期使用炔雌醇（EE）加左炔诺孕酮（LNG），这两种最广泛用于激素避孕药的甾体，会降低大鼠大脑皮质和血浆中的别孕烯醇酮水平，改变 GABA(A) 受体表达并诱导焦虑样行为。我们评估了激素避孕药的哪个成分是导致上述变化的原因。雌性大鼠每天皮下注射 EE（0.030 mg）或 LNG（0.125 mg）一次，共 4 周。与各自的载体处理对照组相比，EE 分别降低大脑皮质中别孕烯醇酮、孕酮和孕烯醇酮的水平 76%、72%和 33%，而在海马体中分别降低 52%、56%和 50%。同样，LNG 分别降低大脑皮质中别孕烯醇酮、孕酮和孕烯醇酮的水平 75%、68%和 33%，以及海马体中分别降低 55%、65%和 60%。LNG 给药增加了大脑皮质和海马体中 γ2 亚基肽的丰度，分别增加了 38%和 59%。此外，LNG 给药，而不是 EE，降低了高架十字迷宫的开放臂停留时间和进入次数，分别减少了 56%和 43%，这是焦虑样行为的一个指标。这些结果表明，长期联合使用 EE/LNG 治疗引起的 GABA(A) 受体亚基表达改变和焦虑样行为似乎是由 LNG 引起的。鉴于 EE 和 LNG 以相似的方式降低别孕烯醇酮水平，这些结果进一步表明，别孕烯醇酮水平的变化与 GABA(A) 受体表达无关。
