Study on the role of endogenous neurosteroids in the regulation of GABAergic function and pathophysiology of stress

内源性神经甾体在GABA能功能调节和应激病理生理学中的作用研究

• 批准号: 15591215
• 负责人: MATSUMOTO Kinzo
• 金额: $ 2.24万
• 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: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591215/
• 关键词: neurosteroid; allopregnanolone; social isolation stress; GABA_A receptor; aggressive behavior; fluoxetine; neuropsychiatric disorder; mice; 不安情動行動; アロブレグナノロン; GABA-A受容体; SKF105111; 5α-reductase

In this study, we investigated physiological and pathophysiological roles of an endogenous neurosteroid, allopregnanolone (ALLO), in the regulation of GABAergic system using protracted social isolation mice as an animal model with dysfunction of neurosteroidogenesis system. Social isolation stress and a 5α-reductase inhibitor SKF105111 (SKF) treatment significantly reduced a threshold dose of picrotoxin to induce convulsion in mice. The effect of SKF was significantly reversed by a small dose of ALLO. The present electrophysiological study revealed that the SKF treatment decreased GABA-induced Cl^-currents and GABA-mediated inhibitory postsynaptic currents in normal mice. Protracted social isolation of mice induced a decrease of brain ALLO content in an isolation period-dependent manner and the extent of the decrease was inversely related to the increase of aggressiveness in this animal group. S-and R-Fluoxetine, selective serotonin reuptake inhibitors, reduced ex vivo serotonin uptake into the brain tissue but there was no difference in the potency between these stereoisomers. On the other hand, both S-and R-fluoxetine mitigated aggressiveness and normalized brain ALLO level in socially isolated mice at lower doses than they inhibited serotonin reuptake. Therefore, our study suggested that the brain ALLO content physiologically upregulates the GABA receptor function and that social isolation stress-induces a reduction of brain ALLO probably causally related with the onset of aggression.

在本研究中，我们使用长期社会隔离小鼠作为神经类固醇生成系统功能障碍的动物模型，研究了内源性神经类固醇四氢孕酮 (ALLO) 在 GABA 能系统调节中的生理和病理生理作用。社交隔离压力和 5α-还原酶抑制剂 SKF105111 (SKF) 治疗显着降低了印防己毒素诱导小鼠惊厥的阈剂量。小剂量的 ALLO 可以显着逆转 SKF 的作用。目前的电生理学研究表明，SKF 治疗降低了正常小鼠中 GABA 诱导的 Cl^-电流和 GABA 介导的抑制性突触后电流。小鼠长期的社会隔离会导致大脑 ALLO 含量以隔离时间依赖性方式减少，并且减少的程度与该动物组攻击性的增加呈负相关。 S-和R-氟西汀是选择性血清素再摄取抑制剂，可减少脑组织对离体血清素的摄取，但这些立体异构体之间的效力没有差异。另一方面，S-氟西汀和 R-氟西汀均能减轻社交孤立小鼠的攻击性，并使大脑 ALLO 水平正常化，其剂量低于抑制血清素再摄取的剂量。因此，我们的研究表明，大脑 ALLO 含量在生理上上调 GABA 受体功能，而社会隔离压力会导致大脑 ALLO 含量减少，这可能与攻击行为的发生存在因果关系。

项目成果

ストレスと睡眠・情動障害:神経ステロイド・allopregnanolone系の関与

压力和睡眠/情感障碍：神经类固醇和四氢孕酮系统的参与

• 发表时间: 2005
• 期刊: 日本薬理学雑誌 (in press)
• 作者: Kenzo Denda;Yukiya Sasaki;Satoshi Asakura;Nobuki Kitagawa;Tsukasa Koyama;松本欣三ほか
• 通讯作者: 松本欣三ほか

Matsumoto K. et al.: "Long-term Social isolation enhances picroroxin seizure susceptibility in mice : Upregularory role of endogenous brain allopregnanolone in GABAergic systems"Pharmacol.Biochern.Behav.. 75. 831-835 (2003)

Matsumoto K. 等人：“长期社会隔离增强了小鼠印吡咯辛癫痫发作的易感性：内源性大脑四氢孕酮在 GABA 能系统中的上调作用”Pharmacol.Biochern.Behav.. 75. 831-835 (2003)

In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine

• DOI: 10.1073/pnas.0337642100
• 发表时间: 2003-02-18
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Pinna, G;Dong, E;Guidotti, A
• 通讯作者: Guidotti, A

Stress and sleep/emotional disorder : possible involvement of neurosteroid allopregnanolone

压力和睡眠/情绪障碍：神经类固醇四氢孕酮可能参与其中

• 期刊: Folia Pharmacologica Japonica (in press)
• 作者: Pinna;G;鈴木雄太郎;Kenzo Denda;傳田健三;鈴木雄太郎;Matsumoto K. et al.
• 通讯作者: Matsumoto K. et al.

Puja G., et al.: "On the putative physiological role of allopregnanolone on GABAA receptor function"Neuropharmacology. 44. 49-55 (2003)

Puja G. 等人：“关于四氢孕酮对 GABAA 受体功能的假定生理作用”神经药理学。