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Effects of neonatal stress and morphine on murine hippocampal gene expression

ABSTRACT: Critically ill preterm infants experience multiple stressors while hospitalized. Morphine is commonly prescribed to ameliorate their pain and stress. We hypothesized that neonatal stress will have a dose-dependent effect on hippocampal gene expression, and these effects will be altered by morphine treatment. Male C57BL/6 mice were exposed to 5 treatment conditions between postnatal day 5 and 9: 1) Control, 2) mild stress + saline, 3) mild stress + morphine, 4) severe stress + saline and 5) severe stress + morphine. Hippocampal RNA was extracted and analyzed using Affymetrix Mouse Gene 1.0 ST Arrays. Single gene analysis and gene set analysis were used to compare groups with validation by qPCR. Stress resulted in enrichment of genes sets related to fear response, oxygen carrying capacity and NMDA receptor synthesis. Morphine downregulated gene sets related to immune function. Stress plus morphine resulted in enrichment of mitochondrial electron transport gene sets, and down-regulation of gene sets related to brain development and growth. We conclude that neonatal stress alone influences hippocampal gene expression, morphine alters a subset of stress-related changes in gene expression and influences other gene sets. Stress plus morphine show interaction effects not present with either stimulus alone. These changes may alter neurodevelopment.

ORGANISM(S): Mus musculus

PROVIDER: GSE50382 | GEO | 2013/08/30

SECONDARY ACCESSION(S): PRJNA217692

REPOSITORIES: GEO

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Project description:Histone acetylation and other modifications of the chromatin are important regulators of gene expression and, consequently, may contribute to drug-induced behaviors and neuroplasticity. Previous studies have shown that a reduction on histone deacetylase (HDAC) activity results on the enhancement of some psychostimulant-induced behaviors. In the present study, we extend those seminal findings by showing that the administration of the HDAC inhibitor sodium butyrate enhances morphine-induced locomotor sensitization and conditioned place preference. In contrast, this compound has no effects on the development of morphine tolerance and dependence. Similar effects were observed for cocaine and ethanol-induced behaviors. These behavioral changes were accompanied by a selective boosting of a component of the transcriptional program activated by chronic morphine administration that included circadian clock genes and other genes relevant in addictive behavior. Our results support an specific role for histone acetylation and the epigenetic modulation of transcription at a reduced number of biologically relevant loci on non-homeostatic, long lasting, drug-induced behavioral plasticity. To further investigate the molecular bases of sodium butyrate action on long-lasting behavioral responses to morphine, we screened for potential substrates of their interaction by performing a genome-wide comparison of the striatal transcriptome after chronic administration of morphine in the absence or presence of sodium butyrate. Striatal tissue was dissected from two months-old Swiss-Albino male mice subjected to behavioral sensitization. Behavioural sensitization: Locomotor sensitization induced by morphine was evaluated using a protocol divided into two phases: induction and challenge. The induction phase involved six trials on alternate days, one trial per day. On each one of these trials, mice received and injection of saline or sodium butyrate (300 mg/kg) immediatedly followed by a second injection of morphine (20 mg/kg). The challenge phases consisted of a single trial conducted 7 days after the last test of the induction phase. In this case, all animals received a single injection of morphine (20 mg/kg). Striatal RNA was extracted 1h after the morphine challenge in groups of four animals that received either saline (N=6) or morphine (N=3), or the sodium butyrate-morphine (N=3) co-treatment during the sensitization induction phase.

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Effects of neonatal stress and morphine on murine hippocampal gene expression

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