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.
Highlights
Schizophrenia is chronic and devastating mental disorder that affects approximately 1% of the world population [1]
We investigated whether transcriptome fingerprint (TFP) in mouse brain could discriminate among different classes of antipsychotics in vivo
Since it is well known that three antipsychotics which have shown the homologous TFPs in Fig. 1 share the high intrinsic activity on D2 receptor (D2R), we examined the time-course TFPs by D2R agonist quinpirole and antagonist sulpiride (Fig. 3a)
Summary
Schizophrenia is chronic and devastating mental disorder that affects approximately 1% of the world population [1]. Since schizophrenia is a unique human dysfunction, it is difficult to judge the similitude of animal models that attempt to replicate aspects of its behavioral abnormality [2]. Combination of these diverse genetic and environmental risk factors may turn this illness into complex brain disorder. Existing antipsychotic drugs have been developed primarily targeting Gi/o-coupled dopamine D2 receptor (D2R) blockade based on dopamine hypothesis [3]. They are effective only for positive symptoms that are mainly due to mesolimbic dopamine hyperactivity in dopamine neurons. A new class of an antipsychotic drug, aripiprazole has affinity for various receptors but somewhat differs from other SDA-type (SDA; serotonin-dopamine antagonist) atypical drugs because it has the highest affinity for D2R receptor [5]
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