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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.

本研究观察了氯氮平长期作用对培养的牛肾上腺髓质细胞功能活性、去甲肾上腺素转运体（NAT）合成及其mRNA表达的影响。用0.1-3.0 μM浓度的氯氮平处理细胞，[^3H]去甲肾上腺素（NA）摄取产生双相变化，即第一相显示在2- 48 h摄取[^3H]NA减少，随后的相显示在72- 168 h摄取增加。氯氮平治疗6 h后，V_m下降<max>至对照组的40%，而[^3H]NA摄取的K_m值无明显变化。而氯氮平治疗96小时后，V_m<max>较对照组增加56%，而K_m无明显变化。[^3 H]去甲丙咪嗪与细胞膜结合的Scatchard图分析显示，氯氮平处理6 h后，细胞膜B_（1/2）降低<max>，而Kd无变化;相反，氯氮平处理96 h后，细胞膜B_（1/2）升高，<max>而Kd无变化。蛋白质合成抑制剂放线菌素D和放线菌酮均能抑制氯氮平（96 h）诱导的[^3H]NA摄取增加。氯氮平处理细胞12- 96 h后，NAT mRNA水平呈浓度依赖性增加（0.1-3.0 μM）。这些结果表明，氯氮平治疗的结果在下调和随后的上调NAT。此外，我们研究了利培酮，血浆游离3-甲氧基-4-羟基苯乙二醇（pMHPG）和血浆高香草酸（pHVA）在34例精神分裂症患者的临床疗效之间的关系。利培酮治疗精神分裂症阴性症状的临床改善与pMHPG和pHVA水平增加相关，利培酮治疗应答者的pMHPG和pHVA水平高于利培酮治疗前无应答者。这些结果表明，利培酮可能通过影响多巴胺能和去甲肾上腺素能神经元，分别改善精神分裂症的阳性和阴性症状。