title: Calcium/calmodulin-dependent kinase II is involved in the facilitating effect of clozapine on NMDA- and electrically evoked responses in the medial prefrontal cortical pyramidal cells.
abstract: Using the method of intracellular recording in in vitro brain slices, we investigated whether calcium/calmodulin-dependent kinase II (CaMKII) is involved in the facilitating action produced by the atypical antipsychotic drug (APD) clozapine on N-methyl-D-aspartate (NMDA)-induced inward currents and electrically evoked excitatory postsynaptic currents (EPSCs) in pyramidal cells of the medial prefrontal cortex (mPFC). The CaMKII inhibitor, KN-93 (N-[2-(N-(4-Chlorocinnamyl)-N-methylaminomethyl)phenyl]-N-[2-hydroxyethyl]-4-methoxybenzenesulfonamide), but not the inactive isomer, KN-92 (2-[N-(4-Methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, phosphate), blocked clozapine's augmenting effect on NMDA-evoked responses in pyramidal cells of the rat mPFC. KN-93 also inhibited the facilitatory effect of clozapine on electrically evoked responses in the pyramidal cells, while KN-92 did not show any effect. Similarly, the calmodulin antagonist W-7 (N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide) inhibited the augmenting effect of clozapine on NMDA- and electrically evoked responses in the pyramidal cells. To further test the role of CaMKII in mediating the augmenting action of clozapine, we performed experiments in alpha-CaMKII mutant and wild-type mice. In contrast to results in pyramidal cells from rats or wild-type mice, clozapine was not able to potentiate NMDA-induced currents in the mPFC pyramidal cells from the CaMKII mutant mouse. Both KN-93 and W-7, but not KN-92, inhibited the augmenting action of clozapine in the pyramidal cells of wild-type mice. Taken together, these results suggest that the facilitating action of clozapine on the NMDA- and electrically evoked responses in pyramidal cells of the mPFC requires activation of CaMKII enzyme.
authors.affiliation: Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Ipe
authors.initials: I
authors.lastname: Ninan
authors.forename: Kent E
authors.initials: KE
authors.lastname: Jardemark
authors.forename: Xiaofu
authors.initials: X
authors.lastname: Liang
authors.forename: Rex Y
authors.initials: RY
authors.lastname: Wang
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003024:Clozapine / Q000494:pharmacology*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D051379:Mice; D009154:Mutation; D016202:N-Methylaspartate / Q000494:pharmacology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000201:enzymology*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D014150:Antipsychotic Agents; D001596:Benzylamines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003024:Clozapine; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D013449:Sulfonamides; C425780:KN 92; C072105:KN 93; D000096926:Benzenesulfonamides; C017967:W 7