ROLE OF EXCITOTOXINS ON BRAIN-ENDOCRINE FUNCTION

兴奋性氨基酸(EAA)最初与神经元有关 死亡，以及许多研究努力致力于它们作为潜在的作用 神经元死亡的中介物。除了它们作为兴奋性毒素的作用外，它还有 很明显，这些物质参与了几个调节 动态平衡机制，包括内分泌。与 多诺索博士，我们的实验室已经为考虑地产代理监管局提供了依据 作为刺激性输入的生理调节系统 LHRH神经元，并由此作为生殖的主要控制器 生理学。在前几年，我们假设监管局的行动 对LHRH分泌的影响主要通过非NMDA受体介导。在……里面 相比之下，几行药理学证据表明，N- 甲基-D-天冬氨酸(NMDA)，NMDA受体的原型激动剂， 在促进黄体生成素分泌方面比其他非 NMDA受体激动剂。在过去的一年里，我们进行了这项工作 明显的矛盾，并评价了NMDA和非 NMDA受体激动剂利用永生化LHRH诱导LHRH分泌 神经元(GT1-7细胞)体外培养。在最初的研究中，我们 使用了NMDA和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 酸(AMPA)作为NMDA和非NMDA受体的特异性激动剂， 分别进行了分析。正如我们小组之前观察到的那样，NMDA无法 对体外培养的GT1-7细胞促性腺激素释放激素分泌的影响 浓度高达20毫米。相反，AMPA刺激LHRH 以剂量依赖的方式释放，最小有效剂量为低 为100毫米。因此，这些观察结果清楚地支持这样一种观点 EAA对LHRH神经元的影响是由非NMDA受体介导的 直接作用于LHRH神经元网络。此外，我们能够 演示抑制性(IAA)和EAA系统之间的相互作用 下丘脑培养的外植体对LHRH分泌的调节 在试管中。事实是1)GT1细胞对AMPA和2) 表达γ-氨基丁酸受体mRNA加强了这一想法 IAA和EAA都建立了双重抑制和刺激系统 作用于LHRH神经元网络。

Excitatory amino acids (EAA) were originally implicated in neuronal death, and many research efforts were devoted to their role as potential mediators of neuronal death. Besides their role as excitotoxins, it has become apparent that these substances participate in several regulatory homeostatic mechanisms including the endocrine. In collaboration with Dr. Donoso, our laboratory has provided the basis for considering the EAA system a physiological regulatory system acting as a stimulatory input to LHRH neurons and, by that, as a major controller of reproductive physiology. During prior years, we postulated that the actions of EAA on LHRH secretion were mediated primarily via non-NMDA receptors. In contrast, several lines of pharmacological evidence indicated that N- methyl-D-aspartic acid (NMDA), the prototype agonist for NMDA receptors, was more potent in increasing LH secretion when compared to other non- NMDA receptor agonists. During this last year, we have undertaken this apparent contradiction and have evaluated the ability of NMDA and non- NMDA receptor agonists to elicit LHRH secretion using immortalized LHRH neurons (GT1-7 cells) incubated in vitro. In the initial studies, we have used NMDA and alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) as specific agonists for NMDA and non-NMDA receptors, respectively. NMDA, as previously observed by our group, was unable to influence LHRH secretion from GT1-7 cells incubated in vitro at concentrations as high as 20 mM. Conversely, AMPA stimulated LHRH release in a dose-dependent manner with a minimum effective dose as low as 100 mM. Therefore, these observations clearly support the notion that the effects of EAA on LHRH neurons are mediated by non-NMDA receptors acting directly on the LHRH neuronal network. Furthermore, we were able to demonstrate an interaction between inhibitory (IAA) and EAA systems in the regulation of LHRH secretion using hypothamalic explants incubated in vitro. The fact that 1) GT1 cells are responsive to AMPA and 2) express gamma-amino-butyric acid receptor mRNA reinforce the idea that both IAA and EAA establish a dual inhibitory and stimulatory system acting upon the LHRH neuronal network.