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Research ArticleNEUROPHARMACOLOGY

Differential Effects of Haloperidol and Clozapine on [3H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Yogesh Dwivedi, Hooriyah S. Rizavi and Ghanshyam N. Pandey
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 197-209; DOI: https://doi.org/10.1124/jpet.301.1.197
Yogesh Dwivedi
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Hooriyah S. Rizavi
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Ghanshyam N. Pandey
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Abstract

The present study was undertaken to examine whether the mechanism of action of typical and atypical antipsychotics is related in their ability to regulate key phosphorylating enzyme of adenylyl cyclase-cAMP pathway, i.e., protein kinase A (PKA). For this purpose, regulatory (R) and catalytic (Cat) activities of PKA and expression of various isoforms of regulatory and catalytic subunits were examined in rat brain after single or chronic (21-day) treatment with haloperidol (HAL, 1 mg/kg) or clozapine (CLOZ, 20 mg/kg). It was observed that chronic but not acute treatment of CLOZ significantly decreased [3H]cAMP binding to the regulatory subunit of PKA as well as catalytic activity of PKA in particulate and cytosol fractions of the rat cortex, hippocampus, and striatum. In these fractions, CLOZ significantly decreased protein levels of selective RIIα-, RIIβ-, and Catβ-subunit isoforms of PKA. These decreases were accompanied by decreases in their respective mRNA expression. In contrast, chronic but not acute treatment of HAL significantly increased [3H]cAMP binding and the catalytic activity of PKA in particulate and cytosol fractions of only the striatum brain area. In addition, chronic treatment of HAL significantly increased mRNA and protein levels of RIIα- and RIIβ-subunit isoforms in the striatum. None of the antipsychotics caused any change in the expression of the Catα-, RIα-, or RIβ-subunit isoform. These results, thus, suggest that HAL and CLOZ differentially regulate PKA catalytic and regulatory activities and the expression of selective catalytic and regulatory subunit isoforms of PKA, which may be associated with their mechanisms of action.

Footnotes

  • This study was supported by Grant KO1 MH01836 from the National Institute of Mental Health and Young Investigator Award from the American Foundation of Suicide Prevention (to Y.D.) and Grant RO1-MH56528 from the National Institute of Mental Health (to G.N.P.).

  • Abbreviations:
    Cat
    catalytic
    CLOZ
    clozapine
    HAL
    haloperidol
    PKA
    protein kinase A
    PKC
    protein kinase C
    R
    regulatory
    ECL
    enhanced chemiluminescence
    EPS
    extrapyramidal side effects
    TD
    tardive dyskinesia
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    AEBSF
    4-(2-aminoethyl)-benzenesulfonyl fluoride
    bp
    base pair(s)
    • Received October 17, 2001.
    • Accepted December 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleNEUROPHARMACOLOGY

Differential Effects of Haloperidol and Clozapine on [3H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Yogesh Dwivedi, Hooriyah S. Rizavi and Ghanshyam N. Pandey
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 197-209; DOI: https://doi.org/10.1124/jpet.301.1.197

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Research ArticleNEUROPHARMACOLOGY

Differential Effects of Haloperidol and Clozapine on [3H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Yogesh Dwivedi, Hooriyah S. Rizavi and Ghanshyam N. Pandey
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 197-209; DOI: https://doi.org/10.1124/jpet.301.1.197
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