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Opiate responses are controlled by interactions of Oprm1 and Fgf12 loci in the murine BXD family: Correspondence to human GWAS findings

ABSTRACT: We analyzed time-dependent behavioral responses to morphine and naloxone obtained from a large family of young adult BXD mice (n = 63–64 strains, including C57BL/6J and DBA/2J parents, n = 4–9/strain) using new whole genome sequencing (WGS)-based genetic markers. Opiate behavioral data include locomotor and behavior responses measured over a four hour period in 15 min bins after an acute morphine injection (50 mg/kg i.p.), followed by naloxone-induced withdrawal (see Philip et al. (2010). Sexes were mapped jointly and independently for males and females using 20,000 markers and linear mixed models that account for kinship structure. We confirmed a highly significant association between locomotor response and a genomic region that overlaps Oprm1 on Chr 10 at 6.8 Mb (LOD of 11.4) 15 to 105 min after injection, with a peak at 75 min. Effects were only weakly dependent of sex. Strains that inherited B haplotypes ran 76 meters farther than those that inherited D haplotypes. We discovered a novel association between a locus on Chr 16 and a late-phase locomotor response 150 min after morphine in both sexes. This locus had a significant but transient epistatic interaction with Oprm1 at 45–90 min—well before its main additive effect was detectable. The Chr 16 locus includes one compelling candidate—fibroblast growth factor 12 (Fgf12). Null mutation of Fgf12 has been shown to cause locomotor deficits (e.g., ataxia). Single nuclei transcriptomic analysis further validated a functional epistatic relationship between Oprm1 and Fgf12, showing that their expression is correlated in a specific subtype of Drd1-expressing medium spiny neurons.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE214388 | GEO | 2023/09/27

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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Opiate responses are controlled by interactions of Oprm1 and Fgf12 loci in the murine BXD family: Correspondence to human GWAS findings

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