PT  - JOURNAL ARTICLE
AU  - Marion Wittmann
AU  - Michael J. Marino
AU  - Darrell A. Henze
AU  - Guy R. Seabrook
AU  - P. Jeffrey Conn
TI  - Clozapine Potentiation of <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor Currents in the Nucleus Accumbens: Role of NR2B and Protein Kinase A/Src Kinases
AID  - 10.1124/jpet.104.080200
DP  - 2005 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 594--603
VI  - 313
IP  - 2
4099  - http://jpet.aspetjournals.org/content/313/2/594.short
4100  - http://jpet.aspetjournals.org/content/313/2/594.full
SO  - J Pharmacol Exp Ther2005 May 01; 313
AB  - Clozapine is an atypical antipsychotic that has a unique clinical profile that distinguishes it from other typical and atypical antipsychotics. At present, the underlying mechanisms of action of clozapine are unclear. Recent studies in the field of schizophrenia suggest that compounds that potentiate N-methyl-d-aspartate (NMDA) receptor function in the appropriate brain regions might be an effective antipsychotic agent. One relevant region in which NMDA receptors play a key role in mediating neurotransmission is the nucleus accumbens. Therefore, we investigated the regulation of NMDA receptor currents and excitatory postsynaptic currents (EPSCs) by clozapine in nucleus accumbens neurons. Whole-cell patch-clamp recordings were performed in rat brain slices. We demonstrate that bath application of clozapine but not haloperidol or the selective 5-hydroxytryptamine 2A antagonist MDL100907 [(R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluoro-phenyl)ethyl]-4-piperidine methanol] induces a robust potentiation of NMDA-evoked currents and of glutamatergic EPSCs and that this potentiation is dependent on dopamine release and postsynaptic activation of D1 receptors. Furthermore, the effect of clozapine is selective for NR2B subtype-containing NMDA receptors and is blocked by the selective Src family kinase inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] and the protein kinase A-selective inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide but not by the protein kinase C-selective inhibitor bisindolylmaleimide I. This effect of clozapine in the nucleus accumbens might underlie the unique clinical profile of this atypical antipsychotic and provides a basis for novel treatment approaches. The American Society for Pharmacology and Experimental Therapeutics