Do atypical antipsychotic drugs improve symptoms of schizophrenia by influencing noradrenergic neurons?

非典型抗精神病药物是否通过影响去甲肾上腺素能神经元来改善精神分裂症的症状？

基本信息

批准号：
13671039
负责人：
NAKAMURA Jun
金额：
$ 2.24万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

The effects of long-term treatment with clozapine on functional activity, synthesis and mRNA of noradrenaline transorter (NAT) were examined in bovine adrenal medullary cells in culture. Treatment of cells with clozapine at 0.1-3.0 μM concentrations produced dual phases of changes in [^3H]noradrenaline(NA) uptake, i.e. the first phase showed a decrease in [^3H]NA uptake at 2-48h, and the following phase showed an increase in uptake at 72-168h. Treatment with clozapine for 6h decreased V_<max> to 40% of the control without changing the K_m value for [^3H]NA uptake. However, treatment with clozapine for 96h increased V_<max> by 56% over the control without a change in K_m. Scatchard plot analysis of [^3H]desipramine(DMI) binding to membranes isolated from cells treated with clozapine for 6h revealed a decrease in B_<max> without any change in K_d ; in contrast, treatment with clozapine for 96h caused an increase in B_<max> without any change in K_d. Both actinomycin D and cycloheximide, which are inhibitors of protein synthesis, suppressed the clozapine (96h)-induced increase in [^3H]NA uptake. Treatment of cells with clozapine for 12-96h increased the level of NAT mRNA in a concentration-dependent manner (0.1-3.0 μM). These findings suggest that treatment with clozapine results in the down-regulation and subsequent up-regulation of NAT. In addition, we examined the relationship among the clinical efficacies of risperidone, plasma free 3-methoxy-4-hydroxyphenylglycol (pMHPG) and plasma homovanillic acid (pHVA) in 34 schizophrenic patients. Clinical improvement in negative symptoms of schizophrenia treated with risperidone has been associated with increased pMHPG and pHVA levels in the responders to risperidone were higher than those of nonresponders before risperidone administration. These results suggest that risperidone might improve positive and negative symptoms in schizophrenia by influencing dopaminergic and noradrenergic neurons, respectively.

氯氮平长期治疗对去甲肾上腺素透射蛋白（NAT）的功能活性，合成和mRNA的影响，在培养中的牛肾上腺髓质细胞中进行了检查。在0.1-3.0μM浓度下用氯氮平治疗细胞的细胞在[^3H]去甲肾上腺素（Na）摄取的变化中产生了双阶段，即第一阶段显示在2-48H时[^3H] Na摄取的降低，并且以下阶段显示在72-168H时摄取的增加。用氯氮平进行6H处理，将V_ <max>降低至对照的40％，而不会更改[^3H] Na摄取的K_M值。但是，用氯氮平治疗96h的治疗比对照组增加了56％，而不会改变k_m。 [^3H]去丙胺（DMI）与从用氯氮平治疗的细胞分离为6H的膜的SCATCHARD图分析显示，B_D>降低了b_ <ax>降低，而k_d却没有任何变化。相反，用氯氮平治疗96H，导致B_ <ax>的增加，而K_D没有任何变化。放线霉素D和环己酰亚胺是蛋白质合成的抑制剂，都抑制了氯氮平（96H）诱导的[^3H] Na摄取的增加。用氯氮平进行12-96H的细胞以浓度依赖性方式（0.1-3.0μm）增加了NAT mRNA的水平。这些发现表明，用氯氮平治疗导致NAT的下调和随后的上调。此外，我们研究了34名精神分裂症患者的利培酮，利培酮，无血浆3-甲氧基-4-羟基苯基甘油（PMHPG）（PMHPG）（PMHPG）（PMHPG）（PMHPG）的临床功效之间的关系。用利培酮治疗的精神分裂症的阴性症状的临床改善与对利培酮的响应者的PMHPG和PHVA水平升高有关，高于利培酮给药之前的无反应者。这些结果表明，利培酮可以分别通过影响多巴胺能和去甲肾上腺素能神经元的影响来改善精神分裂症的阳性和阴性症状。