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Received for publication November 8, 2004.
Revised January 18, 2005.
Accepted for publication January 18, 2005.
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 NMDA receptor function in the appropriate brain regions might be effective antipsychotic agents. One relevant region in which NMDA receptors play a key role in mediating neurotransmission is the nucleus accumbens. We therefore investigated the regulation of NMDA receptor currents and 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 5HT2A antagonist MDL100907 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 and the protein kinase A selective inhibitor H-89, but not by the protein kinase C selective inhibitor BIS 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.
Key words:
atypical antopsychotic, basal ganglia, dopamine, haloperidol, psychosis, schizophrenia
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