Classification of Antipsychotic Drugs by Gene Expression in the Frontal Cortex of Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE1501 | GEO | 2004/09/24
SECONDARY ACCESSION(S): PRJNA90827
REPOSITORIES: GEO
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Project description:Antipsychotic drugs are classified as typical and atypical based on extrapyramidal effects. However, since the frontal cortex is one of the most important regions for antipsychotic actions, this study attempted to classify antipsychotic drugs based on gene expression in the frontal cortex. Chlorpromazine and thioridazine were selected as typical antipsychotics, and olanzapine and quetiapine as atypical antipsychotics. Since these drugs have similar chemical structures, the effect of the basic structure on gene expression can be eliminated. Cluster analysis of microarray experiments showed thioridazine and olanzapine constituted a robust cluster. K-means clustering separated 4-drug-administered mice into chlorpromazine-quetiapine and thioridazine-olanzapine groups. This classification scheme is different from that which is based on criteria currently used to group the typical and atypical drugs and suggests that antipsychotic drugs can be further separated into multiple groups. Experiment Overall Design: Male 13-week-old ddY mice (Japan SLC Co., Hamamatsu, Japan) weighing 38-43 g were used. Animals were housed with free access to standard food in an air-conditioned room under a constant dark-and-light cycle (light: 7:00 a.m. to 7:00 p.m.) at a temperature of 22 to 24°C and 60 to 70% relative humidity. Ether was used for anesthesia during decapitation. All efforts were made to minimize animal suffering and to reduce the number of animals used. The present experiments were carried out after obtaining permission from the Committee of Animal Experimentation of the Graduate School of Medical and Dental Sciences at Kagoshima University. Experiment Overall Design: Doses of 25 mg/kg chlorpromazine HCl (Sigma-Aldrich Co., St. Louis, MO), 25 mg/kg thioridazine HCl (Sigma-Aldrich Co.), 1.25 mg/kg olanzapine (gift from Eli Lilly and Company, Indianapolis, IN) and 18.75 mg/kg quetiapine fumarate (gift from AstraZeneca, Macclesfield, UK) were used in the study. The dosages for these drugs were determined from therapeutically equivalent doses previously reported (Lehman et al, 2003; Woods, 2003). The drugs were dissolved in acetic anhydride and diluted with 0.9% saline, resulting in a final concentration of acetic acid of 0.5%. The drugs were injected intraperitoneally once daily for 28 consecutive days in a volume of 0.1 ml/10 g body weight. Experiment Overall Design: Microarray experiments were performed using an Agilent G4121A Mouse Oligo Microarray Kit (Agilent Technologies, Palo Alto, CA) as per the manufacturerâ??s instructions. The frontal cortex was immediately removed and the RNA was stabilized in RNAlater RNA Stabilization Reagent (Qiagen, Valencia, CA) and stored at -80°C until use. Total RNA was extracted using the RNeasy Mini Kit (Qiagen). The RNA was amplified and labeled by the Low RNA Input Fluorescent Linear Amplification Kit (Agilent). To synthesize cDNA, 200 ng total RNA was used. Vehicle-injected controls were labeled by cyanine 3 (PerkinElmer Life Sciences, Inc., Boston, MA) and drug-injected mice were labeled by cyanine 5 (PerkinElmer Life Sciences, Inc.). Hybridizations to the microarray were performed using the In situ Hybridization Kit Plus (Agilent). Doses of 750 ng cyanine 3-labeled cRNA, 750 ng cyanine 5-labeled cRNA, and control targets were mixed and fragmented in the kitâ??s fragmentation buffer, and then hybridized to the microarrays for 17 hours at 60°C in a hybridization rotator (Agilent) set to rotate at 4 rpm. Microarrays were washed in 6Ã?SSC with 0.005% Triton X-102 at RT for 10 min, followed by 0.1Ã?SSC with 0.005% Triton X-102 at 4°C for 5 min. The slides were dried, and then scanned by the Agilent G2565BA Microarray Scanner System. Data were analyzed using the Agilent Feature Extraction Software version 7.1. A rank consistency filter and LOWESS were used for dye normalization. Control mice and drug-injected mice were processed in parallel. The data discussed in this publication are presented in accordance with the MIAME guidelines (http://www.mged.org/Workgroups/MIAME/miame.html) and were deposited in NCBIs Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/). They can be accessed using the GEO series accession number GSE1501. Experiment Overall Design: Cluster analysis was performed using free software written by M. Eisen (http://rana.lbl.gov/EisenSoftware.htm). The cclust package in the â??Râ?? statistical software system (www.cran.r-project.org) was used to find the most appropriate number of clusters (i.e. â??kâ?? in the k-means clustering).
2008-06-12 | E-GEOD-1501 | biostudies-arrayexpress
Project description:Schizophrenia is a psychiatric disorder that affects more than 21 million people worldwide. It is an incurable disorder and the primary means of managing symptoms is through administration of pharmacological treatments, which consist heavily of antipsychotics. First-generation antipsychotics have the properties of D2 receptor antagonists. Second-generation antipsychotic are antagonists of both D2 and 5HT2 receptors. Recently, there has been increasing interest in the effects of antipsychotics beyond their neuronal targets and oligodendrocytes are one of the main candidates. Thus, our aim was to evaluate the molecular effects of typical and atypical drugs across the proteome of the human oligodendrocyte cell line, MO3.13. For this, we performed a mass spectrometry-based, bottom-up shotgun proteomic analysis to identify differences triggered by typical (chlorpromazine and haloperidol) and atypical (quetiapine and risperidone) antipsychotics. Proteins which showed changes in their expression levels were analyzed in silico using Ingenuity® Pathway Analysis, which implicated dysregulation of canonical pathways for each treatment. Our results shed light on the biochemical pathways involved in the mechanisms of action of these drugs, which may guide the identification of novel biomarkers and the development of new and improved treatments.
2019-11-12 | PXD008892 | Pride
Project description:In this study, a comprehensive evaluation model for studying the cardiac toxicity of antipsychotic drugs was established by using iPSC-CMs. Six antipsychotic drugs, including aripiprazole, risperidone, quetiapine, haloperidol, clozapine, and olanzapine, all induced concentration-dependent QT prolongation in iPSC-CMs upon acute administration, and high concentrations of these drugs caused disorganized sarcomere arrangement in iPSC-CMs.
2024-01-01 | GSE248368 | GEO
Project description:Background. Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell, and pharmacological studies suggest an important overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics in medium spiny neurons (MSNs). Methods. We applied single-cell RNA-sequencing to striatal samples from C57BL/6J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We implemented careful statistical analyses to identify differentially expressed genes in two cell populations identified from the single-cell RNA-sequencing (MSNs and microglia) and applied multiple analysis pipelines to contextualize these findings. Results. Differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) in MSNs from mice treated with olanzapine vs. haloperidol. DEGs were enriched in broad loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses highlighted alternative splicing, mitochondrial function, and neuron and synapse development as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. Conclusions. Our goal was to evaluate connections between schizophrenia genetic findings and cellular gene expression changes following antipsychotic exposure. We found that differential gene expression in MSNs from mice chronically treated with olanzapine converges on similar pathways and gene sets.
2021-04-14 | GSE171977 | GEO
Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways. comparison of olanzapine treated rats vs. control rats for genome-wide DNA methylation changes
2013-11-22 | E-GEOD-52615 | biostudies-arrayexpress
Project description:Analysis of gene expression in the striatum, the liver, the pancreas, and the visceral adipose tissue of mice treated for 28 days with a daily dose of an atypical antipsychotic: risperidone (1 mg/kg) or olanzapine (3.5 mg/kg). Results provide new insights into the molecular mechanisms underlying antipschotic effects, particularly in tissues relevant for antipsychotic-induced metabolic dysregulation. Antipsychotics are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. We used microarrays to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects.
2021-09-08 | GSE180473 | GEO
Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways.
2013-11-22 | GSE52615 | GEO
Project description:Antipsychotics are the main line of treatment for schizophrenia, despite being effective only in about 50% of patients. Additionally, serious side effects may cause medication drop-out, aggravated by a lack of understanding about how these drugs act at molecular level. As proteomics is a suitable tool for studying multifactorial disorders, the main goal was to unravel signaling pathways in blood plasma associated with a positive treatment outcome for the atypical antipsychotics olanzapine and risperidone. Blood plasma was collected from schizophrenia patients six weeks after treatment (T6), and patients were classified as good or poor responders to olanzapine or risperidone, and then samples were compared to each patient's baseline (T0). All samples were analyzed using label-free quantitative shotgun proteomics. Samples were depleted of the 14 most abundant proteins in plasma, were digested, and then submitted to M-Class two-dimensional nano-liquid chromatography, coupled online to a Synapt G2-Si mass spectrometer. Data was obtained in MSE mode (data- independent acquisition) in combination with ion-mobility (HDMSE). The proteins found to be differentially abundant in good responders compared to poor responders for risperidone and olanzapine were functionally analyzed in silico using Ingenuity® Pathway Analysis and were found to be mostly involved with immune system functions. This data can contribute to better understand the biochemical signaling peripherally triggered by antipsychotic medication, and can eventually be used to help improve treatment outcome by predicting patient response as well as through the development of new medication or a combination of drugs that act on the immune system to reduce the duration of poor response periods in patients suffering with schizophrenia.
2020-06-01 | PXD015049 | Pride
Project description:The prefrontal cortex is greatly associated with a wide range of mental health illnesses including schizophrenia, depression, bipolar disorder, anxiety and autism spectrum disorders. It richly expresses neuroreceptors which are the target for typical and atypical antipsychotics. However as the precise mechanism of action of antipsychotic medications are not known, proteomic studies of the effects of antipsychotic drugs on the brain are warranted. In the current study we aimed to characterise protein expression in the adult rodent prefrontal cortex (n=5 per group) following low dose treatment with the atypical antipsychotic Risperidone or saline (control) in adolescence (postnatal days 34-47). The prefrontal cortex was examined by triplicate one hour runs of label-free LC-MS/MS. The raw mass spectral data were analyzed with the MaxQuantTM software. Statistical analysis was carried out using SAS Version 9.1. Functional and pathway analysis was performed with DAVID.nih and Ingenuity Pathway Analysis respectively and the top five most implicated pathways were found to be clathrin mediated endocytosis, the tri cyclic acid cycle, remodelling of epithelial junctions, rho family GTPase signalling and mitochondrial dysfunction.This brief report summarises the proteomic data obtained from the study described, adds to the current repertoire of data available concerning the effects of atypical antipsychotic drugs on the brain and sheds light on their biological mechanisms.
2014-05-13 | PXD000480 | Pride
Project description:Quetiapine is an atypical neuroleptic with a pharmacological profile distinct from classic neuroleptics. It is currently approved for treating patients with schizophrenia, major depression and bipolar I disorder. However, its cellular effects remain elusive. We used microarrays to characterize RNA transcript levels in the brains of mice chronically treated with quetiapine, the neuroleptic haloperidol, or vehicle. We further characterized particular RNA transcripts in cortical cell cultures. Mice were given one of 5 treatments (vehicle, 1 mg/kg haloperidol, 0.3 mg/kg haloperidol, 100 mg/kg quetiapine, 10 mg/kg quetiapine). Pooled tissue samples were used for microarray analysis of gene expression in the frontal cortex (FC) and striatum (STR). Frontal cortex gene targets were subsequently verified with quantitative real-time PCR (qRT-PCR) from the same cohort of mice and an independent cohort.
2013-04-16 | E-GEOD-45229 | biostudies-arrayexpress