Bergeron R, de Montigny C, Debonnel G
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
J Neurosci. 1996 Feb 1;16(3):1193-202. doi: 10.1523/JNEUROSCI.16-03-01193.1996.
We have shown previously that low doses of selective sigma (sigma)-receptor ligands potentiate the excitatory response of pyramidal neurons to NMDA in the CA3 region of the dorsal hippocampus in the rat. Because progesterone competitively displaces the binding of the ligand N-[3H]allyl-normetazocine (SKF-10,047), the present studies were undertaken to determine in vivo the effect of neuroactive steroids on NMDA-induced excitation of rat CA3 pyramidal neurons. Low doses of dehydroepiandrosterone (DHEA) potentiated the NMDA response selectively and dose-dependently. The effect of DHEA was reversed by the selective sigma antagonist N-dipropyl-2-(4-methoxy-3- (2-phenylethoxy)phenyl)-ethylamine monohydrochloride (NE-100) and by haloperidol, but not by spiperone. Progesterone had no effect by itself but reversed, at low doses, the potentiation of the NMDA response induced by DHEA as well as those induced by nonsteroidal sigma ligands. Neither pregnenolone nor pregnenolone sulfate had any effect on the NMDA response--nor did they antagonize the potentiation of the NMDA response induced by DHEA and by nonsteroidal sigma ligands. A pertussis toxin pretreatment, which inactivates Gi/o-proteins, abolished the potentiating effects of DHEA. Ovariectomy enhanced the potentiation of the NMDA response by the nonsteroidal sigma ligand di(2-tolyl)guanidine (DTG). There was a reciprocal occlusion of the effects of DHEA and DTG; DTG did not potentiate the NMDA response further after DHEA, and DHEA did not do so after DTG. These results suggest that some neuroactive steroids modulate the NMDA response via sigma receptors.
我们之前已经表明，低剂量的选择性σ-受体配体可增强大鼠背侧海马CA3区锥体神经元对N-甲基-D-天冬氨酸（NMDA）的兴奋性反应。由于孕酮竞争性取代配体N-[3H]烯丙基去甲氯氮卓（SKF-10,047）的结合，因此进行了本研究以确定神经活性甾体在体内对NMDA诱导的大鼠CA3锥体神经元兴奋的影响。低剂量的脱氢表雄酮（DHEA）选择性且剂量依赖性地增强了NMDA反应。DHEA的作用可被选择性σ拮抗剂N-二丙基-2-（4-甲氧基-3-（2-苯乙氧基）苯基）乙胺盐酸盐（NE-100）和氟哌啶醇逆转，但不能被螺哌隆逆转。孕酮本身无作用，但在低剂量时可逆转DHEA以及非甾体σ配体诱导的NMDA反应增强。孕烯醇酮和硫酸孕烯醇酮对NMDA反应均无影响，它们也不拮抗DHEA和非甾体σ配体诱导的NMDA反应增强。百日咳毒素预处理可使Gi/o蛋白失活，从而消除DHEA的增强作用。卵巢切除术增强了非甾体σ配体二（2-甲苯基）胍（DTG）对NMDA反应的增强作用。DHEA和DTG的作用存在相互阻断；DHEA作用后DTG不再进一步增强NMDA反应，DTG作用后DHEA也不再增强。这些结果表明，一些神经活性甾体通过σ受体调节NMDA反应。
