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Temporal and Spatial Transcriptional Fingerprints by Antipsychotic or Propsychotic Drugs in Mouse Brain

Various types of antipsychotics have been developed for the treatment of schizophrenia since the accidental discovery of the antipsychotic activity of chlorpromazine. Although all clinically effective antipsychotic agents have common properties to interact with the dopamine D2 receptor (D2R) activat...

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Autores principales: Sakuma, Kensuke, Komatsu, Hidetoshi, Maruyama, Minoru, Imaichi, Sachiko, Habata, Yugo, Mori, Masaaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334909/
https://www.ncbi.nlm.nih.gov/pubmed/25693194
http://dx.doi.org/10.1371/journal.pone.0118510
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author Sakuma, Kensuke
Komatsu, Hidetoshi
Maruyama, Minoru
Imaichi, Sachiko
Habata, Yugo
Mori, Masaaki
author_facet Sakuma, Kensuke
Komatsu, Hidetoshi
Maruyama, Minoru
Imaichi, Sachiko
Habata, Yugo
Mori, Masaaki
author_sort Sakuma, Kensuke
collection PubMed
description Various types of antipsychotics have been developed for the treatment of schizophrenia since the accidental discovery of the antipsychotic activity of chlorpromazine. Although all clinically effective antipsychotic agents have common properties to interact with the dopamine D2 receptor (D2R) activation, their precise mechanisms of action remain elusive. Antipsychotics are well known to induce transcriptional changes of immediate early genes (IEGs), raising the possibility that gene expressions play an essential role to improve psychiatric symptoms. Here, we report that while different classes of antipsychotics have complex pharmacological profiles against D2R, they share common transcriptome fingerprint (TFP) profile of IEGs in the murine brain in vivo by quantitative real-time PCR (qPCR). Our data showed that various types of antipsychotics with a profound interaction of D2R including haloperidol (antagonist), olanzapine (antagonist), and aripiprazole (partial agonist) all share common spatial TFPs closely homologous to those of D2R antagonist sulpiride, and elicited greater transcriptional responses in the striatum than in the nucleus accumbens. Meanwhile, D2R agonist quinpirole and propsychotic NMDA antagonists such as MK-801 and phencyclidine (PCP) exhibited the contrasting TFP profiles. Clozapine and propsychotic drug methamphetamine (MAP) displayed peculiar TFPs that reflect their unique pharmacological property. Our results suggest that transcriptional responses are conserved across various types of antipsychotics clinically effective in positive symptoms of schizophrenia and also show that temporal and spatial TFPs may reflect the pharmacological features of the drugs. Thus, we propose that a TFP approach is beneficial to evaluate novel drug candidates for antipsychotic development.
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spelling pubmed-43349092015-02-24 Temporal and Spatial Transcriptional Fingerprints by Antipsychotic or Propsychotic Drugs in Mouse Brain Sakuma, Kensuke Komatsu, Hidetoshi Maruyama, Minoru Imaichi, Sachiko Habata, Yugo Mori, Masaaki PLoS One Research Article Various types of antipsychotics have been developed for the treatment of schizophrenia since the accidental discovery of the antipsychotic activity of chlorpromazine. Although all clinically effective antipsychotic agents have common properties to interact with the dopamine D2 receptor (D2R) activation, their precise mechanisms of action remain elusive. Antipsychotics are well known to induce transcriptional changes of immediate early genes (IEGs), raising the possibility that gene expressions play an essential role to improve psychiatric symptoms. Here, we report that while different classes of antipsychotics have complex pharmacological profiles against D2R, they share common transcriptome fingerprint (TFP) profile of IEGs in the murine brain in vivo by quantitative real-time PCR (qPCR). Our data showed that various types of antipsychotics with a profound interaction of D2R including haloperidol (antagonist), olanzapine (antagonist), and aripiprazole (partial agonist) all share common spatial TFPs closely homologous to those of D2R antagonist sulpiride, and elicited greater transcriptional responses in the striatum than in the nucleus accumbens. Meanwhile, D2R agonist quinpirole and propsychotic NMDA antagonists such as MK-801 and phencyclidine (PCP) exhibited the contrasting TFP profiles. Clozapine and propsychotic drug methamphetamine (MAP) displayed peculiar TFPs that reflect their unique pharmacological property. Our results suggest that transcriptional responses are conserved across various types of antipsychotics clinically effective in positive symptoms of schizophrenia and also show that temporal and spatial TFPs may reflect the pharmacological features of the drugs. Thus, we propose that a TFP approach is beneficial to evaluate novel drug candidates for antipsychotic development. Public Library of Science 2015-02-18 /pmc/articles/PMC4334909/ /pubmed/25693194 http://dx.doi.org/10.1371/journal.pone.0118510 Text en © 2015 Sakuma et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sakuma, Kensuke
Komatsu, Hidetoshi
Maruyama, Minoru
Imaichi, Sachiko
Habata, Yugo
Mori, Masaaki
Temporal and Spatial Transcriptional Fingerprints by Antipsychotic or Propsychotic Drugs in Mouse Brain
title Temporal and Spatial Transcriptional Fingerprints by Antipsychotic or Propsychotic Drugs in Mouse Brain
title_full Temporal and Spatial Transcriptional Fingerprints by Antipsychotic or Propsychotic Drugs in Mouse Brain
title_fullStr Temporal and Spatial Transcriptional Fingerprints by Antipsychotic or Propsychotic Drugs in Mouse Brain
title_full_unstemmed Temporal and Spatial Transcriptional Fingerprints by Antipsychotic or Propsychotic Drugs in Mouse Brain
title_short Temporal and Spatial Transcriptional Fingerprints by Antipsychotic or Propsychotic Drugs in Mouse Brain
title_sort temporal and spatial transcriptional fingerprints by antipsychotic or propsychotic drugs in mouse brain
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334909/
https://www.ncbi.nlm.nih.gov/pubmed/25693194
http://dx.doi.org/10.1371/journal.pone.0118510
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