title: Temporal and spatial transcriptional fingerprints by antipsychotic or propsychotic drugs in mouse brain.
abstract: 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.
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Sakuma
authors.affiliation: Central Nervous System Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Maruyama
authors.affiliation: Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Imaichi
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Habata
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000068180:Aripiprazole / Q000008:administration & dosage / Q000494:pharmacology; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006213:Hallucinogens / Q000008:administration & dosage* / Q000494:pharmacology; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D000077152:Olanzapine; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; D006213:Hallucinogens; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D000068180:Aripiprazole; D010622:Phencyclidine; D006220:Haloperidol; D000077152:Olanzapine