Differential effects of atypical and typical antipsychotic drugs on N-methyl-D-aspartate- and electrically evoked responses in the pyramidal cells of the rat medial prefrontal cortex.

In the present study, we have demonstrated that atypical antipsychotic drugs (APDs, e.g., clozapine, olanzapine, risperidone, and quetiapine) and atypical APD candidates (e.g., M100907 and Y-931) share a common property in facilitating responses evoked by electrical stimulation of the forceps minor and by N-methyl-D-aspartate (NMDA), but not (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), in pyramidal cells of the medial prefrontal cortex (mPFC). The concentrations of these drugs to exert their action are in a clinically relevant range. Although haloperidol has shown a considerably smaller potentiation of NMDA-evoked current at 50 and 100 nM, it consistently depressed the AMPA-induced current. Chlorpromazine and loxapine failed to modulate significantly NMDA- or AMPA-induced current in the pyramidal cells. Moreover, haloperidol and loxapine demonstrated depression of excitatory postsynaptic currents, whereas chlorpromazine did not show any effect. These findings combined indicate that atypical, but not typical, APDs augment glutamatergic neurotransmission in pyramidal cells of the mPFC. We propose that the beneficial effect of atypical APDs in cognitive dysfunction and negative symptoms in schizophrenia is due to their ability to enhance glutamatergic neurotransmission in the PFC and functionally related limbic structures. Our results further suggest the possible use of glutamatergic neurotransmission in the mPFC as a model for screening and studying the action of potential atypical APDs.