ROLE OF EXCITOTOXINS ON BRAIN-ENDOCRINE FUNCTION

兴奋性氨基酸（EAA）最初涉及神经元的 死亡，许多研究工作致力于他们的作用，作为潜在的 神经元死亡的介质。除了作为兴奋性毒素的作用外， 很明显，这些物质参与了一些监管 包括内分泌在内的自我平衡机制。 协同 博士Donoso，我们的实验室为考虑EAA提供了基础 作为刺激输入的生理调节系统 LHRH神经元，并以此作为生殖的主要控制者， physiology. 在过去几年，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 相反，一些药理学证据表明，N- 甲基-D-天冬氨酸（NMDA），NMDA受体的原型激动剂， 在增加LH分泌方面， NMDA受体激动剂。在过去的一年里，我们承担了这一任务， 明显的矛盾，并评价了NMDA和非NMDA的能力， 使用永生化LHRH引发LHRH分泌的NMDA受体激动剂 体外培养的神经元（GT 1 -7细胞）。 在最初的研究中，我们 已经使用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 正如我们小组以前观察到的那样，NMDA不能 影响体外培养GT 1 -7细胞LHRH分泌 浓度高达20 mM。相反，AMPA刺激LHRH 以剂量依赖性方式释放，最低有效剂量为 因此，这些观察结果清楚地支持了以下观点： EAA对LHRH神经元的作用是通过非NMDA受体介导的 直接作用于LHRH神经元网络。此外，我们能够 证明抑制性（IAA）和EAA系统之间的相互作用 在调节LHRH分泌中的作用 体外 1）GT 1细胞对AMPA有反应，2） γ-氨基丁酸受体mRNA的表达强化了这样一种观点， 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.