Weiland N G, Orchinik M, Tanapat P
Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10021, USA.
Neuroscience. 1997 Jun;78(3):653-62. doi: 10.1016/s0306-4522(96)00619-7.
Some of the effects of glucocorticoids on the function and neuronal plasticity of the hippocampus are mediated by N-methyl-D-aspartate receptor activation. We tested the hypothesis that chronic corticosterone administration increases N-methyl-D-aspartate receptor expression in the hippocampus of the rat. We used in situ hybridization histochemistry to measure the messenger RNA levels for the NR1, NR2A and NR2B subunits of the N-methyl-D-aspartate receptor and [3H]dizocilpine maleate (a non-competitive antagonist) binding to measure N-methyl-D-aspartate receptor density. Since corticosterone depresses circulating testosterone levels, we also examined whether the effects of corticosterone are mediated by or interact with the effects of testosterone. In the intact animal, corticosterone increased messenger RNA levels for NR2A and NR2B but not NR1 subunits of the N-methyl-D-aspartate receptor in all regions of the hippocampus. Testosterone had no significant effect on messenger RNA levels of any of the subunits. The subunit composition determines the functional and pharmacological properties of the N-methyl-D-aspartate receptor. We used ifenprodil inhibition of [3H]dizocilpine maleate binding, which has been used to distinguish NR2A- from NR2B-containing receptors, to determine whether corticosterone altered the proportion of high- and low-affinity sites for ifenprodil in parallel with the changes in subunit messenger RNA levels. Corticosterone increased the density of [3H]dizocilpine maleate binding sites without changing the dissociation constant for [3H]dizocilpine maleate or the proportion of high- and low-affinity sites for ifenprodil. These data suggest that the effects of corticosterone on hippocampal function are mediated, in part, by parallel increases in NR2A and NR2B subunit levels and the number of receptor channel binding sites.
糖皮质激素对海马体功能和神经元可塑性的一些影响是由N-甲基-D-天冬氨酸受体激活介导的。我们检验了以下假设:长期给予皮质酮会增加大鼠海马体中N-甲基-D-天冬氨酸受体的表达。我们使用原位杂交组织化学来测量N-甲基-D-天冬氨酸受体NR1、NR2A和NR2B亚基的信使核糖核酸水平,并使用[3H]马来酸氯氮平(一种非竞争性拮抗剂)结合来测量N-甲基-D-天冬氨酸受体密度。由于皮质酮会降低循环睾酮水平,我们还研究了皮质酮的作用是否由睾酮的作用介导或与其相互作用。在完整动物中,皮质酮增加了海马体所有区域中N-甲基-D-天冬氨酸受体NR2A和NR2B亚基的信使核糖核酸水平,但未增加NR1亚基的信使核糖核酸水平。睾酮对任何亚基的信使核糖核酸水平均无显著影响。亚基组成决定了N-甲基-D-天冬氨酸受体的功能和药理特性。我们使用ifenprodil抑制[3H]马来酸氯氮平结合(该方法已用于区分含NR2A和含NR2B的受体)来确定皮质酮是否与亚基信使核糖核酸水平的变化平行地改变了ifenprodil高亲和力和低亲和力位点的比例。皮质酮增加了[3H]马来酸氯氮平结合位点的密度,但未改变[3H]马来酸氯氮平的解离常数或ifenprodil高亲和力和低亲和力位点的比例。这些数据表明,皮质酮对海马体功能的影响部分是由NR2A和NR2B亚基水平以及受体通道结合位点数量的平行增加介导的。