Mechanism of pharmacological action of nootropics in the hippocampus

使用依赖性突触效能的增强被称为长时程增强。发生在海马体中的长期增强被认为是一种与学习和记忆有关的细胞机制。由于在苔藓纤维-CA3系统中观察到的长期增强是由低浓度的脑功能增强药物增强的，因此可以想象苔藓纤维和CA3锥体细胞之间的突触是这些药物的共同作用部位之一。因此，本项目作为阐明脑功能增强药物在海马区的药理作用机制的一个步骤，得到了以下结果：1。联苯醚是一种脑功能增强药物，可增加豚鼠海马苔藓纤维末端高K^+诱导的l -谷氨酸释放。这种增加可能至少部分是由苔藓纤维末端蛋白激酶C的激活介导的，因为它被一种激酶抑制剂H-7阻断，而双星烯在苔藓纤维末端产生蛋白激酶C从细胞质到膜的易位。在不含苔藓状纤维末端的常规突触体中，双美烯并没有引起l -谷氨酸释放的增加，也没有引起蛋白激酶C的易位。[^3H]双甲醚在豚鼠海马中存在特异性结合位点，且这些结合位点在CA3中的密度高于CAl。[^3H]双甲醚的高亲和力结合位点可能不是单胺摄取位点，因为它们在丙咪嗪存在时被观察到。在1 ~ 1000 nM处，[^3H]联苯醚对[^3H]联苯醚的特异性结合有抑制作用，而长春西汀、吲哚嗪、伊地苯酮、吡拉西坦和hopatenate钙对[^3H]联苯醚的特异性结合没有抑制作用。

The use-dependent strengthening of a synaptic efficacy is known as a long-term potentiation. The long-term potentiation that occurs in the hippocampus is thought to be a cellular mechanisms associated with learning and memory. Since the long-term potentiation observed in the mossy fiber-CA3 system is potentiated by low concentrations of brain function potentiating drugs, it is conceivable that synapse between mossy fibers and CA3 pyramidal cells is one of common sites of actions of these drugs. Therefore, this project was conducted as a step to elucidate the mechanisms of pharmacological actions of brain function potentiating drugs in the hippocampus and the following results have been gotten.1. Bifemelane, a brain function potentiating drug, increased the high K^+ evoked release of L-glutamate from the mossy fiber terminals in the hippocampus of the guinea-pig. Such an increase may be at least partly mediated with the activation of protein kinase C in the mossy fiber terminals, as it was blocked by a kinase inhibitor, H-7, and bifemelane produced the translocation of protein kinase C from cytosol to membrane in the mossy fiber terminals. Bifemelane did not produce an increase in the evoked release of L-glutamate from nor translocation of protein kinase C in conventional synaptosomes that dose not contain mossy fiber terminals.2. There were specific binding sites for [^3H]bifemelane in the hippocampus of the guinea-pig and the density of such binding sites were higher in the CA3 than in the CAl. A high affinity binding sites for [^3H]bifemelane may not be monoamine uptake sites, as they were observed in the presence of imipramine. The specific binding of [^3H]bifemelane was inhibited by bifemelane at 1-1000 nM, but not by vinpocetine, indeloxazine, idebenone, piracetam and Ca hopatenate.