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 rat brain.
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.
Dwivedi
Y
Y
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Pandey
G N
GN
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes; D008297:Male; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism*; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D011493:Protein Kinase C; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D003024:Clozapine; D006220:Haloperidol; D002746:Chlorpromazine