Study on the role of emotional stress for the pathogenesis of psychiatric disorders. -To clarify the relationship between emotional stress and central monoaminergic/peptidergic neural systems using animal models-

本研究的目的是通过在体微透析、放射免疫分析、原位杂交和北方印迹等方法，阐明条件性恐惧应激对中枢单胺能和肽能系统的影响，并检测神经系统的功能定位。1）选择性5-羟色胺再摄取抑制剂（SSRIs）减少了条件性冻结，这是焦虑的一个指标，在治疗性血浆锂水平下，亚慢性锂预处理增强了这些抗焦虑作用，亚慢性锂预处理也增强了阿托宁1A激动剂的抗焦虑作用。体内微透析研究表明，亚慢性锂处理增加了细胞外5-羟色胺的基础水平，并对SSRI诱导的细胞外5-羟色胺的增加产生累加效应。2）在条件性恐惧模型中测试了单胺氧化酶抑制剂（MAOI）的抗焦虑作用。MAO-A抑制剂或MAO-B抑制剂不诱导抗焦虑作用，但非选择性MAOIs以及MAO-A和MAO-B抑制剂的组合具有抗焦虑作用。在体微透析研究表明，MAO-A和MAO-B抑制剂的组合诱导细胞外5-羟色胺的增加比任何一种单独的抑制剂。3）锂和SSRI处理增加大鼠纹状体多巴胺2受体mRNA的水平和多巴胺2受体基因的转录速率。

The purpose of this study is to clarify the effect of conditioned fear stress on central monoaminergic and peptidergic systems using in vivo microdialysis, radioimmunoassay, in situ hybridization, and Northern Blot in discrete brain regions and to examine functional localization of neural systems.1) Selective serotonin reuptake inhibitors (SSRIs) reduced conditioned freezing, an index of anxiety, and these anxiolytic effects were enhanced by subchronic lithium pretreatment at the therapeutic plasma lithium levels.The anxiolytic effects of serotonin1A agonists were also enhanced by subchronic lithium pretreatment. In vivo microdialysis studies showed that subchronic lithium treatment increased basal levels of extracellular serotonin and induced additive effects on SSRI-induced increases in extracellular serotonin.2) The anxiolytic effects of monoamine oxidase inhibitors (MAOIs) were tested in the conditioned fear model. MAO-A inhibitors or MAO-B inhibitors did not induce anxiolytic effects, but non-selective MAOIs and the combination of MAO-A and MAO-B inhibitors were anxiolytic. In vivo microdialysis studies showed that the combination of MAO-A and MAO-B inhibitors induced more increases in extracellular serotonin than either inhibitor alone did.3) Lithium and SSRI treatment increased the level of dopamine2 receptor mRNA and the transcription rate of the dopamine2 receptor gene in the rat striatum.