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

研究了长期氯氮平对培养的牛肾上腺髓细胞功能活性、去甲肾上腺素转运蛋白（NAT）合成及mRNA表达的影响。0.1 ~ 3.0 μM浓度氯氮平对细胞的[^3H]去甲肾上腺素（NA）摄取发生两期变化，即第一期[^3H]NA摄取在2 ~ 48h时减少，后一期在72 ~ 168h时增加。氯氮平治疗6h后，V_<max>降低至对照组的40%，但未改变[^3H]NA摄取的K_m值。然而，氯氮平治疗96小时使V_<max>比对照组增加56%，K_m没有变化。氯氮平处理6h后，地西帕明（DMI）与细胞分离膜结合的Scatchard图分析显示，B_<max>下降，但K_d没有变化；相比之下，氯氮平治疗96小时导致B_<max>升高，但K_d没有变化。放线菌素D和环己亚胺都是蛋白质合成的抑制剂，抑制氯氮平（96h）诱导的[^3H]NA摄取的增加。氯氮平作用细胞12 ~ 96h后，natmrna水平呈浓度依赖性升高（0.1 ~ 3.0 μM）。这些结果表明，氯氮平治疗导致了NAT的下调和随后的上调。此外，我们检测了利培酮、血浆游离3-甲氧基-4-羟基苯基乙二醇（pMHPG）和血浆高香草酸（pHVA）在34例精神分裂症患者中的临床疗效。使用利培酮治疗的精神分裂症阴性症状的临床改善与利培酮应答者的pMHPG和pHVA水平升高有关，在给予利培酮之前，这些患者的pMHPG和pHVA水平高于无应答者。这些结果表明，利培酮可能通过影响多巴胺能神经元和去甲肾上腺素能神经元来改善精神分裂症的阳性和阴性症状。

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.