Abstract
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 α and ε 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 α, γ, and ε 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 β1 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 α and ε 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.
Footnotes
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Send reprint requests to: Ghanshyam N. Pandey, Ph.D., Professor of Pharmacology, Psychiatric Institute, Department of Psychiatry, University of llinois at Chicago, 1601 West Taylor St., Chicago, IL 60612. E-mail:gpandey{at}psych.uic.edu
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1 This study was supported by a grant from the National Institute of Mental Health (RO1-MH-56528).
- Abbreviations:
- HAL
- haloperidol
- IP3
- inositol 1,4,5-trisphosphate
- PDBu
- phorbol 12,13-dibutyrate
- PI
- phosphatidylinositol
- PIP2
- phosphatidylinositol 4,5-bisphosphate
- PLC
- phospholipase C
- PKC
- protein kinase C
- CLOZ
- clozapine
- CPZ
- chlorpromazine
- G protein
- guanine nucleotide binding protein
- bp
- base pair
- Received May 17, 1999.
- Accepted July 15, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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