Dataset Information

Psychotropic drug-induced gene expression alterations in mouse striatum II

ABSTRACT: To identify the molecular mechanisms that may initiate therapeutic effects, whole-genome expression profiling (Illumina Mouse WG-6 microarrays) of drug-induced alterations in the mouse brain was undertaken, with a focus on the time-course (1, 2, 4 and 8h) of gene expression changes produced by eighteen major psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. The resulting database is freely accessible at www.genes2mind.org. Bioinformatics approaches led to the identification of three main drug-responsive genomic networks and indicated neurobiological pathways that mediate the alterations in transcription. Each tested psychotropic drug was characterized by a unique gene network expression profile related to its neuropharmacological properties. Functional links that connect expression of the networks to the development of neuronal adaptations (MAPK signaling pathway), control of brain metabolism (adipocytokine pathway), and organization of cell projections (mTOR pathway) were found. The additional data-sets are available at GEOX1 and GEOX2.

ORGANISM(S): Mus musculus

PROVIDER: GSE48954 | GEO | 2013/07/18

SECONDARY ACCESSION(S): PRJNA212393

REPOSITORIES: GEO

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Project description:To identify the molecular mechanisms that may initiate therapeutic effects, whole-genome expression profiling (Illumina Mouse WG-6 microarrays) of drug-induced alterations in the mouse brain was undertaken, with a focus on the time-course (1, 2, 4 and 8h) of gene expression changes produced by eighteen major psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. The resulting database is freely accessible at www.genes2mind.org. Bioinformatics approaches led to the identification of three main drug-responsive genomic networks and indicated neurobiological pathways that mediate the alterations in transcription. Each tested psychotropic drug was characterized by a unique gene network expression profile related to its neuropharmacological properties. Functional links that connect expression of the networks to the development of neuronal adaptations (MAPK signaling pathway), control of brain metabolism (adipocytokine pathway), and organization of cell projections (mTOR pathway) were found. The additional data-sets are available at GEOX1 and GEOX2. The microarray experiment was performed to analyze time-course of drug-induced transcriptional response in C57BL/6J mouse striatum. Three antidepressants (bupropion 20 mg/kg, tranylcypromine 20 mg/kg, mianserin 20 mg/kg, i.p.), three anxiolytics (diazepam 5 mg/kg, buspirone 10 mg/kg, hydroxyzine 10 mg/kg, i.p.), and three antipsychotics (clozapine 3 mg/kg, risperidone 0.5 mg/kg, haloperidol 1 mg/kg) were selected for the comparison. Drug doses were previously reported as effective in mice and further tested in our laboratory. To analyze dynamics of early, intermediate and relatively late changes of mRNA abundance the experiment was performed in four time points (1, 2, 4 and 8h after drug administration). To exclude influence of drug injection and circadian rhythm on gene expression profile, control groups of saline or tween (1% Tween 80) treated and naïve animals were prepared for each time point. Design of the experiment assumed pooling of two animals per each array and using of three independent arrays per group. To provide appropriate balance in the whole dataset groups were equally divided between the array hybridization batches.

Project description:To identify the molecular mechanisms that may initiate therapeutic effects, whole-genome expression profiling (Illumina Mouse WG-6 microarrays) of drug-induced alterations in the mouse brain was undertaken, with a focus on the time-course (1, 2, 4 and 8h) of gene expression changes produced by eighteen major psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. The resulting database is freely accessible at www.genes2mind.org. Bioinformatics approaches led to the identification of three main drug-responsive genomic networks and indicated neurobiological pathways that mediate the alterations in transcription. Each tested psychotropic drug was characterized by a unique gene network expression profile related to its neuropharmacological properties. Functional links that connect expression of the networks to the development of neuronal adaptations (MAPK signaling pathway), control of brain metabolism (adipocytokine pathway), and organization of cell projections (mTOR pathway) were found. The additional data-sets are available at GEOX1 and GEOX2. The microarray experiment was performed to analyze time-course of drug-induced transcriptional response in C57BL/6J mouse striatum. Three antidepressants (imipramine 10 mg/kg, fluoxetine 20 mg/kg and tianeptine 20 mg/kg, i.p.) were selected for the comparison. Drug doses were previously reported as effective in mice and further tested in our laboratory. To analyze dynamics of early, intermediate and relatively late changes of mRNA abundance the experiment was performed in four time points (1, 2, 4 and 8h after drug administration). To exclude influence of drug injection and circadian rhythm on gene expression profile, control groups of saline treated and naïve animals were prepared for each time point. Design of the experiment assumed pooling of two animals per each array and using of three independent arrays per group. To provide appropriate balance in the whole dataset groups were equally divided between the array hybridization batches.

Project description:Abstract: Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces life-long pathologies. Here, we addressed this question by combining human RNA-seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic β cells permanently reduces their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex-specific epigenetic reprogramming of serotonin-related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production. Synopsis: The abuse of illicit drugs is a major societal problem, including their continued use during pregnancy. Even though harmful effects of commonly-used psychostimulants to the unborn fetus have been postulated, if and how maternal exposure to illicit psychostimulants during pregnancy could reprogram the fetal pancreas and limit glucose metabolism and tolerance for life in affected offspring remain unknown. Here, we combine human and mouse data to outline the sex-specific epigenetic deregulation of serotonin signaling-related gene regulatory networks, which leads to reduced insulin production postnatally. • As little as episodic intrauterine psychostimulant exposure is sufficient to permanently limit beta cell function in postnatal female rather than mouse male offspring. • The serotonin transporter, rather than the dopamine transporter, is identified as a molecular target of psychostimulants in fetal beta cells and in beta cell-like cellular models. • Psychostimulants adversely affect protein serotonylation in beta-cell models. • Altered DNA methylation and accessibility link the life-long deregulation of transcription factors and genes shaping serotonin signaling with reduced functionality in beta cells.