Biphasic modulation of NMDA-induced responses in pyramidal cells of the medial prefrontal cortex by Y-931, a potential atypical antipsychotic drug.
Similar to the effects produced by the atypical antipsychotic drugs (APDs) clozapine and olanzapine, Y-931 [8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine maleate, a purported atypical APD] effectively facilitated N-methyl-D-aspartate (NMDA)-induced, but not (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-evoked, responses in pyramidal cells of the rat medial prefrontal cortex (mPFC). Similar to olanzapine and clozapine, the concentration-response curve of Y-931 in these experiments was biphasic. At present, the mechanisms behind the biphasic modulatory actions of Y-931 and olanzapine on NMDA-induced currents in the mPFC are not clear. In addition to augmenting NMDA responses, Y-931 prevented the phencyclidine (PCP)-induced block of the NMDA responses and increased the amplitudes and durations of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation of the forceps minor. Overall, our findings suggest that APDs, particularly the atypical ones, share a common property in that they facilitate NMDA receptor-mediated transmission in the mPFC and perhaps other functionally related limbic structures as well, which could be the cellular basis for their ability to alleviate some schizophrenic negative symptoms and cognitive dysfunctions.
Jardemark
K E
KE
Department of Psychiatry and Behavioral Science, SUNY at Stony Brook, Stony Brook, New York 11794-8790, USA. kjardemark@mail.psychiatry.sunysb.edu
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Ninan
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Wang
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
C434584:8-fluoro-12-(4-methylpiperazin-1-yl)-6H-(1)benzothieno(2,3-b)(1,5)benzodiazepine; D014150:Antipsychotic Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D001569:Benzodiazepines; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D010622:Phencyclidine