Dopaminergic dysfunction in the prefrontal cortex (PFC) has been implicated in the pathophysiology of schizophrenia. On the other hand, administration of the NMDAR antagonist phencyclidine (PCP) impairs PFC functions and induces a broad range of schizophrenic-like symptoms, thus has been widely used as an animal model for schizophrenia. This study sought to determine the mechanism by which PCP may alter the dopaminergic functions in PFC. In control rats, activation of dopamine D4 receptors produced a significant suppression of NMDA receptor transmission in PFC pyramidal neurons, which was dependent on the inhibition of active CaMKII. However, in PCP-treated rats, the D4 modulation of NMDA receptors was significantly impaired, with the concomitant loss of D4 regulation of CaMKII activity. In contrast, the D4 modulation of voltage-dependent Ca2+ channels was intact following PCP administration. Furthermore, treatment with the antipsychotic drug clozapine restored the D4 regulation of NMDA receptors in PCP-treated rats. These findings suggest that the selective disruption of the interaction between D4 and NMDA receptors in the PCP model, which is attributable to the impaired D4-mediated downstream signaling, may contribute to the aberrant PFC neuronal activity in schizophrenia.