Molecular biological study on modulatory effects of psychotropic agents on biosynthesis and metabolism of neuropeptides

各种精神药物通过细胞内第二信使系统（例如，蛋白激酶A和C）。另一方面，神经肽（即，内源性的、神经元功能的调节剂）通过其前体的基因表达来合成。在本研究计划中，我们试图研究第二信使系统在神经肽前体基因表达中的调节作用。主要结果如下：1）在大鼠端脑，前胆囊收缩素原基因表达在出生后发育的早期阶段增加。此外，基因表达存在明显的性别差异，可能是由于性腺类固醇激素的作用。2）大鼠原代培养细胞中前脑啡肽原基因的表达受蛋白激酶A和C系统激活剂的控制。3）糖皮质激素（即，具有神经营养作用的类固醇激素）增强了由蛋白激酶A系统介导的前脑啡肽原基因的激活，而不是由蛋白激酶C系统介导的激活。4）前脑啡肽原基因在大鼠生殖细胞中高度表达，并且表达几乎不受蛋白激酶系统的控制。在生殖细胞中表达的信使RNA具有独特的结构，提示前脑啡肽原基因的表达受细胞内第二信使系统相互作用的控制。其他神经肽的基因表达可能受到类似机制的控制，因此应计划进一步的研究。

Various kinds of psychotropic agents exert their modulatory effects on neuronal functions through intracellular second messenger systems (e.g., protein kinases A and C). On the other hand, neuropeptides (i.e., endogenous, modulators of neuronal functions) are synthesized through the gene expression of their precursors. In this research project, we have attempted to examine modulatory roles of the second messenger systems in the gene expression of neuropeptide precursors. Major findings obtained are as follows:1) In the rat telencephalon, the preprocholecystokinin gene expression is increased at early stages of postnatal development. In addition, there is a distinct sex-related difference in the gene expression, presumably due to effect of gonadal steroid hormones.2) The expression of preproenkephalin gene in rat primary cultured cells is controlled by the activators for protein kinase A and C systems.3) Glucocorticoids (i.e., steroid hormones having neurotropic actions) potentiate,the preproenkephalin gene activation mediated by protein kinase A system, but not that mediated by protein kinase C system.4) The preproenkephalin gene is highly expressed in the rat germ cells, and the expression is hardly controlled by the protein kinase systems. The messenger RNA expressed in the germ cells shows a unique structure.Above findings indicate that the expression of preproenkephalin gene is controlled by the interactions between intracellular second messenger systems. Gene expression of other neuropeptides may be controlled by similar mechanisms, and further studies should thus be planned.