Gulinello M, Gong Q H, Smith S S
SUNY Downstate Medical Center, Dept. of Physiology and Pharmacology, 450 Clarkson Avenue, 11203-2098, Brooklyn, NY, USA.
Neuropharmacology. 2002 Sep;43(4):701-14. doi: 10.1016/s0028-3908(02)00171-5.
Withdrawal from the neurosteroid 3alpha,5alpha-allopregnanolone after chronic administration of progesterone increases anxiety in female rats and up-regulates the alpha4 subunit of the GABA(A) receptor (GABA(A)-R) in the hippocampus. We investigated if these phenomena would also occur in male rats. Progesterone withdrawal (PWD) induced higher alpha4 subunit expression in the hippocampus of both male and female rats, in association with increased anxiety (assessed in the elevated plus maze) comparable to effects previously reported. Because alpha4-containing GABA(A)-R are insensitive to the benzodiazepine (BDZ) lorazepam (LZM), and are positively modulated by flumazenil (FLU, a BDZ antagonist), we therefore tested the effects of these compounds following PWD. Using whole-cell patch clamp techniques, LZM-potentiation of GABA ((EC20))-gated current was markedly reduced in CA1 pyramidal cells of male rats undergoing PWD compared to controls, whereas FLU had no effect on GABA-gated current in control animals but increased it in PWD animals. Behaviorally, both male and female rats were significantly less sensitive to the anxiolytic effects of LZM. In contrast, FLU demonstrated significant anxiolytic effects following PWD. These data suggest that neurosteroid regulation of the alpha4 GABA(A)-R subunit may be a relevant mechanism underlying anxiety disorders, and that this phenomenon is not sex-specific.
长期给予孕酮后停用神经甾体3α,5α-别孕烷醇酮会增加雌性大鼠的焦虑，并上调海马中GABA(A)受体（GABA(A)-R）的α4亚基。我们研究了这些现象是否也会在雄性大鼠中出现。孕酮撤药（PWD）诱导雄性和雌性大鼠海马中α4亚基表达升高，同时焦虑增加（在高架十字迷宫中评估），与先前报道的效应相当。由于含α4的GABA(A)-R对苯二氮䓬（BDZ）劳拉西泮（LZM）不敏感，且受氟马西尼（FLU，一种BDZ拮抗剂）正向调节，因此我们测试了PWD后这些化合物的作用。使用全细胞膜片钳技术，与对照组相比，经历PWD的雄性大鼠CA1锥体细胞中LZM对GABA（(EC20)）门控电流的增强作用明显降低，而FLU对对照动物的GABA门控电流无影响，但在PWD动物中增加了该电流。行为学上，雄性和雌性大鼠对LZM的抗焦虑作用均明显不敏感。相反，FLU在PWD后表现出显著的抗焦虑作用。这些数据表明，神经甾体对α4 GABA(A)-R亚基的调节可能是焦虑症潜在的相关机制，且这种现象并非性别特异性。
