Neurosteroid regulation of GABAィイD2AィエD2 receptor function and its application to development of new psychotropic drugs.

神经类固醇对GABAD2AD2受体功能的调节及其在新型精神药物开发中的应用

• 批准号: 10672148
• 负责人: MATSUMOTO Kinzo
• 金额: $ 2.43万
• 依托单位: Toyama Medical and Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672148/
• 关键词: Neurosteroids; Social isolation stress; Majonoside-R2; Psychological stress; GABAィイD2AィエD2 receptors; Endogenous benzodiazepine receptor ligand; Pentobarbital sleep; Fluoxetine; Neurosteroids; social isolation stress; psychological stress; majo

This study aimed to clarify a role of the neurosteroid system in the regulation of GABAィイD2AィエD2 receptor in normal and psychologically stressed animals, and to obtain basic information on whether the neurosteroid system can be a target for developing new psychotropic drugs. Mice were exposed to social isolation stress (SIS) or psychological stress with communication box paradigm (SCBP). Group-housed mice (GR) were used as normal control.SIS decreased the brain content of the positive allosteric GABAィイD2AィエD2 receptor modulator allopregnanolone (ALLO), and shortened pentobarbital (PB) sleep. Fluoxetine reversed SIS-induced changes in the ALLO content and PB sleep without affecting these parameters in GR. Blockade of ALLO biosynthesis shortened PB- and muscimol-induced sleep, and suppressed GABAィイD2AィエD2-gated current in the pyramidal neurons. DBI, an endogenous peptide capable of interacting with central and mitochondrial benzodiazepine receptors (MBR), shortened PB sleep in GR without … More affecting socially isolated mice. SIS suppressed DBI gene expression in the hypothalamus. The MBR agonist FGIN-l-27 normalized PB sleeping time in socially isolated mice and the effect was antagonized by the a negative allosteric GABAィイD2AィエD2 receptor modulator pregnenolone sulfate (PS). SCBP increased lipid peroxidation products in the brain via activating neuronal nitric oxide synthase. Majonoside-R2 suppressed this increase in a PS reversible manner.These results demonstrate that ALLO has a permissive role in the GABAergic neurotransmission in the normal animals and that the decrease in the ALLO content impairs the GABAィイD2AィエD2 receptor function, resulting in a psycho-pathophysiological state. Moreover, it is likely that SIS causes a decrease in PB sleep partly by increasing DBI activity and that DBI gene expression in the hypothalamus is regulated by a negative feedback mechanism. Moreover, the involvement of neurosteroids in the effect of fluoxetine and majonoside-R2 suggests that the neurosteroid system could be a new target for psychotropic drug development. Less

本研究旨在阐明神经类固醇系统在正常和心理应激动物的GABAィイD2AィエD2受体调节中的作用，并获得神经类固醇系统是否可以作为开发新精神药物的靶点的基础信息。小鼠承受社会孤立压力（SIS）或交流盒范式（SCBP）心理压力。群养小鼠（GR）用作正常对照。SIS降低了大脑中正变构GABAィイD2AィエD2受体调节剂四氢孕酮（ALLO）的含量，并缩短了戊巴比妥（PB）睡眠。氟西汀逆转了 SIS 引起的 ALLO 含量和 PB 睡眠的变化，而不影响 GR 中的这些参数。阻断 ALLO 生物合成可缩短 PB 和蝇蕈醇诱导的睡眠，并抑制锥体神经元中的 GABAiiD2AiiD2 门控电流。 DBI 是一种能够与中枢和线粒体苯二氮卓受体 (MBR) 相互作用的内源性肽，可缩短 GR 中的 PB 睡眠，而不会影响社交孤立的小鼠。 SIS 抑制下丘脑中的 DBI 基因表达。 MBR 激动剂 FGIN-1-27 使社会孤立小鼠的 PB 睡眠时间正常化，并且该作用被负变构 GABAiiD2AiiD2 受体调节剂孕烯醇酮硫酸盐 (PS) 拮抗。 SCBP 通过激活神经元一氧化氮合酶增加大脑中的脂质过氧化产物。 Majonoside-R2 以可逆的方式抑制 PS 的这种增加。这些结果表明 ALLO 在正常动物的 GABA 能神经传递中具有许可作用，并且 ALLO 含量的减少会损害 GABAiiD2AiiD2 受体功能，导致精神病理生理状态。此外，SIS 可能部分通过增加 DBI 活性而导致 PB 睡眠减少，并且下丘脑中的 DBI 基因表达受到负反馈机制的调节。此外，神经类固醇参与氟西汀和majonoside-R2的作用表明神经类固醇系统可能成为精神药物开发的新目标。较少的

项目成果

Kaori Yobimoto et al.: "Suppressive effects of Vietnamese ginseng saponin and its major component majonoside-R2 on psychological stress-induced enhancement of lipid peroxidation in the mouse brain"Pharmacol. Biochem. Behav.. (in Press). (2000)

Kaori Yobimoto 等人：“越南人参皂苷及其主要成分 majonoside-R2 对心理应激诱导的小鼠大脑脂质过氧化增强的抑制作用”Pharmacol。

Matsumoto K., Yobimoto K., Huong N. T. T., Abdel-Fattah Mohamed A. -F., Hien T. V., Watanabe H.: "Psychological stress-induced enhancement of brain lipid peroxidation via nitric oxide systems and its modulation by anxiolytic and anxiogenic drugs in mice."

Matsumoto K.、Yobimoto K.、Huong N. T. T.、Abdel-Fattah Mohamed A. -F.、Hien T. V.、Watanabe H.：“心理应激通过一氧化氮系统诱导脑脂质过氧化增强及其通过抗焦虑和抗焦虑药物的调节

Erbo Dong et al.: "Involvement of diazepam binding inhibitor an its fragment octadecaneuropeptide in social isolation stress-induced decrease in pentobarbital sleep in mice"Life Sci.. 64. 1779-1784 (1999)

Erbo Dong 等：“地西泮结合抑制剂及其片段十八烷神经肽参与社会隔离应激诱导的小鼠戊巴比妥睡眠减少”生命科学 64. 1779-1784 (1999)

Huong N. T. T., Matsumoto K., Watanabe H.: "The antistress effect of majonoside-R2, a major saponin component of Vietnamese ginseng : Neuronal mechanism of action."Meth. Find. Exp. Clin. Pharmacol.. 20(1). 65-76 (1998)

Huong N. T. T.、Matsumoto K.、Watanabe H.：“越南人参的主要皂苷成分 majonoside-R2 的抗应激作用：神经元作用机制。”

Graziano Pinna et al.: "Brain allopregnanolone regulates the potency of the GABA_A receptor agonist muscimol."Neuropharmacology. 39. 440-448 (2000)

Graziano Pinna 等人：“大脑四氢孕酮调节 GABA_A 受体激动剂蝇蕈醇的效力。”神经药理学。