Dwivedi Y, Pandey G N
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
J Pharmacol Exp Ther. 1999 Nov;291(2):688-704.
The effects of acute (single) and chronic (21-day) administration of haloperidol (HAL), chlorpromazine (CPZ), or clozapine (CLOZ) on components of the phosphoinositide (PI)-signaling pathway were studied in rat brain. Chronic administration of HAL decreased protein kinase C (PKC) activity and mRNA and protein levels of PKC alpha and epsilon isozymes in both membrane and cytosol fractions of cortex, hippocampus, and striatum. Chronic administration of CPZ, however, decreased PKC activity only in the membrane fraction of cortex, hippocampus, and striatum, and had no effect on the levels of any PKC isozymes. On the other hand, chronic administration of CLOZ decreased PKC activity and mRNA and protein levels of PKC alpha, gamma, and epsilon isozymes in membrane and cytosol fractions of cortex, hippocampus, and cerebellum. Studies of the effects on phospholipase C (PLC) revealed that only chronic administration of CPZ significantly decreased PI-PLC activity and mRNA and protein levels of the specific PLC beta(1) isozyme in membrane and cytosol fractions of cortex, hippocampus, cerebellum, and striatum. Acute-treatment data suggest that CPZ or CLOZ had no significant effects on PI-PLC or PKC; however, HAL translocated PKC, as evidenced from increased PKC activity and protein levels of PKC alpha and epsilon isozymes in the membrane fraction and the decrease in these parameters in the cytosol fraction of cortex, hippocampus, and striatum. Our results thus suggest that the interaction of antipsychotic drugs with PKC and PLC may be associated with their mechanisms of action.
研究了急性（单次）和慢性（21天）给予氟哌啶醇（HAL）、氯丙嗪（CPZ）或氯氮平（CLOZ）对大鼠脑内磷酸肌醇（PI）信号通路各组分的影响。慢性给予HAL可降低皮质、海马和纹状体膜和胞质组分中蛋白激酶C（PKC）的活性以及PKCα和ε同工酶的mRNA和蛋白水平。然而，慢性给予CPZ仅降低皮质、海马和纹状体膜组分中的PKC活性，对任何PKC同工酶的水平均无影响。另一方面，慢性给予CLOZ可降低皮质、海马和小脑膜和胞质组分中PKC的活性以及PKCα、γ和ε同工酶的mRNA和蛋白水平。对磷脂酶C（PLC）影响的研究表明，仅慢性给予CPZ可显著降低皮质、海马、小脑和纹状体膜和胞质组分中PI-PLC的活性以及特异性PLCβ(1)同工酶的mRNA和蛋白水平。急性处理数据表明，CPZ或CLOZ对PI-PLC或PKC无显著影响；然而，HAL使PKC易位，这可从皮质、海马和纹状体膜组分中PKC活性增加以及PKCα和ε同工酶蛋白水平升高，以及这些参数在胞质组分中的降低得到证明。因此，我们的结果表明，抗精神病药物与PKC和PLC的相互作用可能与其作用机制有关。
