In the present study, we demonstrate that, in a concentration-dependent manner,
M100907 (formerly
MDL 100907, a highly selective
5-HT2A receptor antagonist and a purported atypical
antipsychotic drug [APD]), but not its much less active stereoisomer M100009, completely prevents or markedly reverses the
phencyclidine (PCP)-induced blockade of
N-methyl-D-aspartate (
NMDA) responses in pyramidal neurons of the medial prefrontal cortex (mPFC). Furthermore, the atypical APD
clozapine, but not the typical APD
haloperidol or
raclopride (a selective
dopamine D2,3 receptor antagonist), mimicked the action of
M100907, preventing the PCP-induced effect. These results suggest that
M100907 might be an
antidote for treating the PCP-induced psychotomimetic state that closely resembles
schizophrenia; they could also account for the
antipsychotic potential of
M100907. Furthermore, our results suggest that the prototype (
clozapine) and a candidate (
M100907) atypical APDs might be effective in ameliorating schizophrenic symptoms including cognitive and neuropsychological deficits, which are induced in humans who
abuse PCP. We hypothesize that the ability of
M100907 and
clozapine to prevent or reverse the PCP-induced blockade of the
NMDA receptor channel is attributed to their 5-HT2A receptors antagonizing property. Therefore, with further systematic studies, the ability of compounds to prevent or reverse PCP's blockade of
NMDA responses may prove to be an effective electrophysiological model for screening potential atypical APDs and predicting their therapeutic efficacy in cognitive deficits.