Masonis A E, McCarthy M P
Dept. of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway.
J Pharmacol Exp Ther. 1996 Oct;279(1):186-93.
We have recently demonstrated that androgenic/anabolic steroids modulate in vitro ligand binding to the benzodiazepine binding site(s) associated with the gamma-aminobutyric acidA (GABAA) receptor complex (Masonis and McCarthy, 1995). One androgenic/anabolic steroid in particular, stanozolol, appears to stabilize the GABAA receptor in a moderate-affinity state for benzodiazepine binding. In the present study, we demonstrate the effects of stanozolol on the functional responsiveness of the GABAA receptor. After pre-incubation with stanozolol, we observed a decrease in the Emax and EC50 values for GABA-stimulated 36Cl- influx into cortical synaptoneurosomes. Moreover, in the presence of stanozolol, flunitrazepam-enhanced GABA-stimulated 36Cl- influx was lost, and the GABAA receptor was stabilized in a functional state that was resistant to further desensitization by agonist. Stanozolol does not appear to reduce GABA-stimulated 36Cl- influx by acting as a channel blocker at the well-characterized channel blocker binding site, as illustrated by the GABA-sensitive biphasic effects of stanozolol on [35S] t-butylbicyclophosphorothionate binding. These results demonstrate a novel, nongenomic mechanism for androgenic/anabolic steroidal modulation of CNS function.
我们最近证实，雄激素/合成代谢类固醇可在体外调节与γ-氨基丁酸A（GABAA）受体复合物相关的苯二氮䓬结合位点的配体结合（马索尼斯和麦卡锡，1995年）。特别是一种雄激素/合成代谢类固醇司坦唑醇，似乎能使GABAA受体稳定在对苯二氮䓬结合具有中等亲和力的状态。在本研究中，我们展示了司坦唑醇对GABAA受体功能反应性的影响。在用司坦唑醇预孵育后，我们观察到GABA刺激的36Cl-流入皮质突触神经体的Emax和EC50值降低。此外，在司坦唑醇存在的情况下，氟硝西泮增强的GABA刺激的36Cl-流入消失，并且GABAA受体稳定在一种对激动剂进一步脱敏具有抗性的功能状态。司坦唑醇似乎并不是通过在特征明确的通道阻滞剂结合位点作为通道阻滞剂来减少GABA刺激的36Cl-流入，如司坦唑醇对[35S]叔丁基双环磷硫代酸盐结合的GABA敏感性双相效应所示。这些结果证明了雄激素/合成代谢类固醇调节中枢神经系统功能的一种新的非基因组机制。
