Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms as well as by cognitive deficits. From the pharmacological standpoint, there are important differences among antipsychotic drugs (APD): typical compound are potent in treating positive symptoms, whereas atypical drugs appear to be effective also on negative symptoms and have a better profile in terms of side-effects. Such differences can result from their receptor profiles as antagonists of different neurotransmitter receptors. The majority of these drugs share one common pharmacological property, namely the blockade of dopamine D 2 receptors although many APD's interact with other neurotransmitter receptors, including serotonin 5HT 2 , dopamine D 1 and D 4 , cholinergic and histaminergic receptors. However other neurotransmitter systems can be important for the action of APD's. Among the others, based on anatomical and neurochemical data, an involvement of the glutamate system has been put forward. Glutamate is used as neurotransmitter in brain regions, such as cerebral cortex and hippocampus, that are crucial for the integration of emotional responses and whose function appears to be compromised in schizophrenia. Moreover, the observation that N-methyl-D-aspartate receptor (NMDA-R) blockers, such as ketamine and phencyclidine, can induce psychosis in normal subjects suggests that this glutamate receptor subtype might be involved in schizophrenia and that dysfunctions in dopamine/glutamate interactions may contribute to the abnormalities observed in this psychiatric disorder. Although APD's do not interact directly with glutamate receptors, they may alter glutamatergic neurotransmission in specific brain structures that are important for their antipsychotic activity. One possible approach to investigate the involvement of glutamate in the mechanism of action of APD's is based on the determination of glutamate receptor expression profile in response to antipsychotic drug treatment. The recent cloning of different glutamate receptors has given the opportunity to investigate this aspect in more detail. The N-methyl-D-aspartate (NMDA) receptor is a glutamate-gated cation-specific ion channel which plays a key role in many forms of neuronal plasticity. This receptor is formed by two families of subunits (NR-1 and NR-2): NR-1 serves as the key subunit that possesses the characteristic features of the NMDA-R, whereas NR-2 subunits potentiate receptor activity in heteromeric configurations and are regarded as modulatory. According to the expression pattern of these subunits, NMDA-R's with different functional and pharmacological properties may exist. Changes in receptor composition may therefore be part of adaptive mechanisms taking place in different physiological as well as pathological situations. Using a sensitive RNase protection assay, we have investigated the gene expression for NMDA receptor subunits following acute and chronic treatment of rats with typical (haloperidol) and atypical (clozapine and quetiapine) APD's. Male Sprague Dawley rats were injected a single time (acute) or for 21 days (chronic) with haloperidol (1 mg/kg), clozapine (10 or 30 mg/kg) or quetiapine (25 mg/kg) before being sacrificed by decapitation. A single injection of haloperidol, clozapine as well as quetiapine elicited a significant increase in the mRNA levels for NR-1 and NR-2B in the nucleus accumbens, but only haloperidol was able to elevate the mRNA levels for NR-2A and NR-2B in the hippocampus. Following chronic administration, we detected significant differences in the regulatory pattern of NR-1 and NR-2 subunits. Haloperidol produced a significant elevation of their mRNA levels in striatum whereas clozapine, consistent with its relatively weaker influence on nigro-striatal dopamine function, did not change the expression of NR subunits in this region. Both APD's were able to decrease the expression of NR-2 subunits in the hypothalamus, without changing the levels of their mRNA's at hippocampal level. Interestingly the atypical drugs clozapine and quetiapine, but not haloperidol, were able to decrease the expression of NR-1 and NR-2C in the nucleus accumbens and in frontal cortex. The specific action of these APD's on such brain structures may be relevant for the clinical profile of atypical antipsychotics. The possibility that NMDA-R can be a potential target of APD's treatment in the prefrontal cortex is also supported by a recent report showing a significant alteration in the proportion of NR-2 subunits in the prefrontal cortex of schizophrenic patients.In summary, the regulation of NMDA receptor subunits, and possibly of other glutamate receptors, in specific brain regions can provide a molecular tool to discriminate among different compounds used for the cure of schizophrenia and may represent a novel and important mechanism through which APD's exert some of their effects on brain function.