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

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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.