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Study on the pharmacological basis for the effect of psychological stress in the early life stage on response to psychotropic drugs

生命早期心理应激对精神药物反应影响的药理学基础研究

基本信息

批准号：
17591219
负责人：
KUROKI Toshihide
金额：
$ 2.25万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17591219/
关键词：
stress development brain microdialysis dopamine norepinephrine drug response serotonin receptor corticotropin releasing factor

项目摘要

This study aims to elucidate the mechanism for the influence of psychological stress in the early life stage on pharmacological response to psychotropic drugs as a sequel of the enduring changes in development of the neuronal network involving emotion.Fist, we examined the pharmacological basis for the ability of atypical antipsychotic drugs to induce dopamine release in rat prefrontal cortex, using in vivo microdialysis. The results suggest that, depending on the manner of binding to presynaptic dopamine-D2 autoreceptors, different types of atypical antipsychotic drugs may have distinct effects on the activity of dopamine neurons projecting from the ventral tegmental area to the prefrontal cortex. Moreover, the results from the experiment of local application with atypical antipsychotic drugs into the medial prefrontal cortex suggest that the interaction between weak D2 antagonism and potent serotonin (5-HT) 1A receptor agonism within the local circuitry of the prefrontal cortex may c … More ontribute to the ability of clozapine and aripiprazole to increase prefrontal dopamine release. Therefore, expression and maturation of these monoamine receptor subtypes in the prefrontal cortex during the developmental stage may be involved in the clinical response to psychotropic drugs.Second, psychological stress in the early life stage has been thought to increase expression of corticotrophin-releasing factor (CRF), resulting in the enduring effect on development of the neuronal network. We therefore investigated the effect of the selective antagonist for CRF1 receptors on dopamine release in the prefrontal cortex of adult and young rats. As the results, a significant difference in the ability of CRF1 antagonist to modulate stress-induced dopamine release was found between adult (age of six to eight weeks) and young (age of three weeks) rats. These results suggest that the physiological role of CRF1 receptors in the dopaminergic response to stressors may change during the developmental stage. Further studies are needed because individual responses to stressors differed widely. Less

本研究旨在阐明在生命早期阶段的心理应激对精神药物的药理学反应的影响机制，作为涉及emotion.Fist的神经元网络的发展的持久变化的续集，我们研究了非典型抗精神病药物的药理学基础的能力，诱导多巴胺释放在大鼠前额皮质，使用在体微透析。结果表明，根据结合到突触前多巴胺D2自身受体的方式，不同类型的非典型抗精神病药物可能对从腹侧被盖区投射到前额皮质的多巴胺神经元的活性具有不同的影响。此外，将非典型抗精神病药物局部应用于内侧前额叶皮层的实验结果表明，在前额叶皮层局部回路中，弱D2拮抗作用和强5-HT 1A受体激动作用之间的相互作用可能与脑内的神经元兴奋有关。 ...更多信息有助于氯氮平和阿立哌唑增加前额多巴胺释放的能力。因此，这些单胺受体亚型在发育阶段的前额叶皮层的表达和成熟可能参与了精神药物的临床反应。其次，早期生活阶段的心理应激被认为会增加促肾上腺皮质激素释放因子（corticotrophin-releasing factor，CRF）的表达，从而对神经元网络的发育产生持久的影响。因此，我们研究了CRF 1受体的选择性拮抗剂对成年和年轻大鼠前额叶皮层多巴胺释放的影响。作为结果，发现CRF 1拮抗剂调节应激诱导的多巴胺释放的能力在成年（6至8周龄）和年轻（3周龄）大鼠之间存在显著差异。这些结果表明，CRF 1受体在多巴胺能反应的压力源的生理作用可能会改变在发育阶段。需要进一步的研究，因为个体对压力源的反应差异很大。少