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Electrophysiological and behavioral pharmacology study on biological pathogenesis of contextual fear and anxiety

情境恐惧和焦虑生物学发病机制的电生理学和行为药理学研究

基本信息

批准号：
09671012
负责人：
KASAMO Kimihiro
金额：
$ 2.05万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Conditioned-fear induced freezing behavior in an animal model of fear or anxiety generated by memory and cognition. Previous brain lesioning studies have shown that the hippocampus plays important role roles in the expression of the freezing behavior. In these 3 years, we have shown the following issues in animal studies using male adult Wistar rats :・ It is well known that 5-HT1A agonists, SSRIs and benzodiazepines have anxiolytic properties. Among these anxiolytic drugs, 5-HT1A agonist buspirone, and SSRIs sertraline and fluvoxamine suppress the spontaneous firing activity of dorsal hippocampus CA1 pyramidal neurons whereas the effect of a benzodiazepine derivative alprazolam varied across the tested neurons.・ Using urethane anesthetized rats, we examined effects of buspirone and alprazolam on the firing activity of the CA1 pyramidal neurons induced by microiontophoretic applications of acetylcholine (Ach), NMDA, quisqualate or kainate. Buspirone inhibited the firing activities induced by any of these compounds whereas alprazolam suppressed the kainate-induced firing activity only. These observations indicated that stimulation of kainate receptors in the rat brain might play a crucial role in generating the conditioned fear.・ Indeed, an antagonist for AMPA/kainate receptor CNQX inhibited the conditioned fear stress-induced freezing behavior in our behavioral experiments.・ During such freezing behavior, the spontaneous firing activity of dorsal hippocampus CA1pyramidal neurons was decreased by the facilitated stimulations of postsynapitc 5-HT1A receptors that would have resulted from an increase in extracellular 5-HT.

条件性恐惧在由记忆和认知产生的恐惧或焦虑的动物模型中导致冻结行为。以往的脑损害研究表明，海马区在冰冻行为的表达中起着重要作用。在这三年中，我们在使用成年雄性Wistar大鼠进行的动物研究中发现了以下问题：·众所周知，5-HT1A激动剂、SSRI和苯二氮卓类药物具有抗焦虑特性。在这些抗焦虑药物中，5-HT1a激动剂丁螺环酮、SSRIs舍曲林和氟伏沙明抑制背侧海马CA1区锥体神经元的自发放电活动，而苯二氮卓类衍生物阿普唑仑的作用因受试神经元而异。·利用乌拉坦麻醉大鼠，观察丁螺环酮和阿普唑仑对乙酰胆碱(Ach)、N-甲基-D-天门冬氨酸(NMDA)、喹乙醇或海人藻酸盐诱导的CA1区锥体神经元放电活动的影响。丁螺环酮抑制上述化合物的放电活动，而阿普唑仑仅抑制红藻氨酸诱发的放电活动。这些观察表明，刺激大鼠大脑中的海人酸受体可能在产生条件性恐惧中发挥关键作用。·的确，在我们的行为实验中，AMPA/海人藻酸受体CNQX的拮抗剂抑制了条件性恐惧应激诱导的冰冻行为。·在这种冰冻行为中，突触后5-HT1a受体的易化刺激降低了背侧海马CA1区锥体神经元的自发放电活动，而突触后5-HT1a受体可能是细胞外5-羟色胺增加的结果。