Effects of treatment with haloperidol, chlorpromazine, and clozapine on protein kinase C (PKC) and phosphoinositide-specific phospholipase C (PI-PLC)activity and on mRNA and protein expression of PKC and PLC isozymes in ratbrain

The effects of acute (single) and chronic (21-day) administration of halope ridol (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 a nd protein levels of PKC alpha and epsilon isozymes in both membrane and cy tosol fractions of cortex, hippocampus, and striatum. Chronic administratio n 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 P KC isozymes. On the other hand, chronic administration of CLOZ decreased PK C activity and mRNA and protein levels of PKC alpha, gamma, and epsilon iso zymes in membrane and cytosol fractions of cortex, hippocampus, and cerebel lum. Studies of the effects on phospholipase C (PLC) revealed that only chr onic administration of CPZ significantly decreased PI-PLC activity and mRNA and protein levels of the specific PLC beta(1) isozyme in membrane and cyt osol fractions of cortex, hippocampus, cerebellum, and striatum. Acute-trea tment data suggest that CPZ or CLOZ had no significant effects on PI-PLC or PKC; however, HAL translocated PKC, as evidenced from increased PKC activi ty and protein levels of PKC a and e isozymes in the membrane fraction and the decrease in these parameters in the cytosol fraction of cortex, hippoca mpus, and striatum. Our results thus suggest that the interaction of antips ychotic drugs with PKC and PLC may be associated with their mechanisms of a ction.