M100907 and clozapine, but not haloperidol or raclopride, prevent phencyclidine-induced blockade of NMDA responses in pyramidal neurons of the rat medial prefrontal cortical slice.
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.
Wang
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Department of Psychiatry and Behavioral Science, SUNY ast Stony Brook 11794-8790, USA.
Liang
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D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D018408:Patch-Clamp Techniques; D010622:Phencyclidine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects; D012457:Salicylamides / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D012457:Salicylamides; D012702:Serotonin Antagonists; D020891:Raclopride; C079049:volinanserin; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol