Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat

MacDonald, Matthew L.; Eaton, Molly; Dudman, Joshua T.; Konradi, Christine

doi:10.1016/j.biopsych.2005.01.022

Cited by 72 publications

(53 citation statements)

References 74 publications

(89 reference statements)

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“…First, limited sample size makes it difficult to determine significant drug effect when comparing treated versus untreated subjects or correlating APD treatment with gene expression. In addition, chronic APD treatment is thought to induce long term cellular and neuroadaptive changes that would influence gene expression (Hyman and Nestler 1996;MacDonald et al 2005). Precedence for persisting drug effects exists in the dopamine system literature, e.g.…”

Section: Discussionmentioning

confidence: 99%

AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs

O’Connor

Muly

Arnold

et al. 2007

Schizophrenia Research

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Disturbances in glutamate neurotransmission are thought to be one of the major contributing factors to the pathophysiology of schizophrenia. In the dorsolateral prefrontal cortex (DLPFC), glutamate neurotransmission is largely mediated by AMPA receptors. Data regarding alterations of subunit expression in the brains of patients with schizophrenia remain equivocal. This may be due to differences in technique sensitivity, endogenous control selection for normalization of data, or effect of antipsychotic drug treatment in different cohorts of schizophrenia. This study attempted to address these issues by examining the expression of AMPA receptor subunits and splice variants in the DLPFC of two schizophrenia cohorts using quantitative PCR (qPCR) with normalization to the geometric mean of multiple endogenous controls. In addition, a non-human primate model of chronic antipsychotic drug administration was used to determine the extent to which the transcript expression may be altered by antipsychotic drug treatment in the primate DLPFC. AMPA receptor subunits and flip and/or flop splice variants were not significantly different in the DLPFC of schizophrenia subjects versus controls in either of the two cohorts. However, in rhesus monkeys chronically treated with antipsychotic drugs, clozapine treatment significantly decreased GRIA1 and increased GRIA3 mRNA expression, while both clozapine and haloperidol increased the expression of GRIA2 subunit mRNA. Expression of AMPA receptor splice variants was not significantly altered by antipsychotic drug administration. This is the first study to show that AMPA receptor subunit mRNAs in the primate DLPFC are altered by antipsychotic drug administration. Antipsychotic drug induced alterations may help explain differences in human post-mortem studies regarding AMPA receptor subunit expression and provide some insight into the mechanism of action of antipsychotic drugs.

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Section: Discussionmentioning

confidence: 99%

AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs

O’Connor

Muly

Arnold

et al. 2007

Schizophrenia Research

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“…326 Microarray studies in rats treated with clozapine or haloperidol found an increase in the transcription of genes coding for proteins involved in synaptic plasticity and activity in the frontal cortex. 327 Different gene upregulation profiles were observed after clozapine and haloperidol treatment in two separate studies by the same team of investigators. 328,329 Interestingly, these studies found that Synapsin II, a gene implicated in schizophrenia, was upregulated by haloperidol, and the glucose-dependent insulinotropic polypeptide (GIP), a gene that may have a role in glucose intolerance and weight gain, was upregulated by clozapine.…”

Section: Discerning the Mechanism Of Action Of Antipsychoticsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…Previous similar microarray studies investigating the effects of chronic administration of antipsychotics in brains of rodents are limited and yet informative (Chen and Chen, 2005;Chong et al, 2002;Kontkanen et al, 2002;MacDonald et al, 2005;Thomas et al, 2003). Chong et al (2004) showed that chronic administration of clozapine in rats for 28 days upregulated mRNA and protein for rat glia-derived nexin in brains of exposed animals.…”

Section: Introductionmentioning

confidence: 99%

“…The authors showed that both drugs increased genes associated with lipid metabolism, such as apolipoprotein D, the mouse homolog of oxysterol-binding protein-like protein 8, and lysophosphatidic acid acyltransferase (Thomas et al, 2003). MacDonald et al (2005) investigated gene profiles in the frontal cortex and striatum of rats in response to chronic exposure to haloperidol and clozapine. Several genes coding for presynaptic proteins including VAMP1, syntaxin 1A, and SNAP 25 were upregulated in the frontal cortex, potentially increasing synaptic plasticity and synaptic activity (MacDonald et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…MacDonald et al (2005) investigated gene profiles in the frontal cortex and striatum of rats in response to chronic exposure to haloperidol and clozapine. Several genes coding for presynaptic proteins including VAMP1, syntaxin 1A, and SNAP 25 were upregulated in the frontal cortex, potentially increasing synaptic plasticity and synaptic activity (MacDonald et al, 2005). Finally, in the most recent publication, Chen and Chen (2005) analyzed gene expression profiles in the frontal cortex of rats administered risperidone for 1-4 weeks.…”

Section: Introductionmentioning

confidence: 99%

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Chronic Olanzapine Treatment Causes Differential Expression of Genes in Frontal Cortex of Rats as Revealed by DNA Microarray Technique

Fatemi

Reutiman

Folsom

et al. 2006

Neuropsychopharmacol

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Recent emerging biochemical data indicate that several important neuroregulatory genes and proteins may be involved in the etiology of schizophrenia and bipolar disorder. Additionally, the same genes appear to be targets of several psychotropic medications that are used to treat these disorders. Recent DNA microarray studies show that genes involved in synaptic neurotransmission, signal transduction, and glutamate/GABA regulation may be differentially regulated in brains of subjects with schizophrenia. We hypothesized that chronic administration of olanzapine to rats would alter expression of various genes that may be involved in the etiology of schizophrenia and mood disorders. Rats were administered olanzapine (N ¼ 20, 2 mg/kg/day) or sterile saline intraperitoneally (N ¼ 20) daily for 21 days. Control and olanzapine-treated frontal cortices were analyzed using cDNA microarray technology. The results showed significant downregulation of 31 genes and upregulation of 38 genes by greater than two-fold in the drug-treated brains vs controls. Our results provide evidence for altered regulation of genes involved with signal transduction and cell communication, metabolism and energy pathways, transport, immune response, nucleic acid metabolism, and neuronal growth factors. Real-time quantitative RT-PCR analysis verified the direction and magnitude of change in six genes of interest: calbindin 3, homer 1, regulator of G-protein signaling (RGS) 2, pyruvate kinase, Reelin and insulin 2. Western blotting showed significant upregulation in protein products for Reelin 410 and Reelin 180 kDa and downregulation for NMDA3B and RGS2. Our results show for the first time that olanzapine causes changes in levels of several important genes that may be involved in the etiology and treatment of schizophrenia and other psychiatric disorders.

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Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat

Abstract: We found an increase in the transcription of genes coding for proteins involved in synaptic plasticity and synaptic activity in the FC. We furthermore found that the gene expression profile of APDs is different between FC and striatum.

Cited by 72 publications

References 74 publications

AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs

AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Chronic Olanzapine Treatment Causes Differential Expression of Genes in Frontal Cortex of Rats as Revealed by DNA Microarray Technique

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