piperidines and phorbol

We have previously shown that the atypical antipsychotic drug clozapine facilitates N-methyl-D-aspartate (NMDA)- and electrically evoked responses in pyramidal cells of the medial prefrontal cortex (mPFC). In the present study, we investigated the role of protein kinase C (PKC) in the action of clozapine. Bath administration of the PKC activator phorbol-12-myristate 13-acetate (PMA), but not the inactive isomer 4alpha-PMA, significantly enhanced the NMDA-evoked inward current and electrically evoked excitatory postsynaptic currents. Chelerythrine, a selective blocker of PKC, completely prevented the potentiating action produced by either clozapine or PMA on these currents in the mPFC cells. Intracellular injection of the PKC inhibitor PKC-I, but not the control substance PKC-S, through the recording electrode totally blocked clozapine's potentiating effect, indicating that a post-synaptic expressed PKC is critically involved in the augmenting action of clozapine on NMDA-evoked currents. Of the PKC inhibitor PKC-I, but not the control substance PKC-S, through the recording electrode totally blocked clozapine's potentiating effect, indicating that a post-synaptic expressed PKC is critically involved in the augmenting action of clozapine on NMDA-evoked currents. To further test the role of PKC in mediating the augmenting action of clozapine, we performed experiments in PKCgamma mutant and wild-type mice. In contrast to results in pyramidal cells from rats or wild-type mice, neither clozapine nor PMA was able to potentiate NMDA-induced currents in the mPFC from the PKCgamma mutant mice. Taken together, these results suggest that the PKC signal transduction pathway is critically involved in the facilitating action of clozapine on the NMDA-induced responses in pyramidal cells of the mPFC.

Topics: Alkaloids; Animals; Benzophenanthridines; Clozapine; Drug Interactions; Electric Stimulation; Electrophysiology; Enzyme Activators; Enzyme Inhibitors; Evoked Potentials; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Fluorobenzenes; GABA Antagonists; gamma-Aminobutyric Acid; In Vitro Techniques; Mice; Mice, Knockout; Mice, Mutant Strains; N-Methylaspartate; Peptide Fragments; Phenanthridines; Phorbols; Piperidines; Protein Kinase C; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Tetradecanoylphorbol Acetate; Time Factors