Quantitative trait loci mapping was used to identify the chromosomal location of genes which contribute to oral morphine preference (in a two-bottle choice paradigm) of C57BL/6J mice, compared to DBA/2J mice. An F2 intercross of these two strains (606 mice) was phenotyped for morphine preference and those mice demonstrating extreme values for morphine consumption (the highest and lowest 7.7%) were genotyped for 157 murine microsatellite polymorphisms. Maximum likelihood methods revealed three loci on murine chromosomes 1, 6 and 10 which are responsible for nearly 85% of the genetic variance observed between the two parental strains.
"We estimated the narrow-sense heritability of OXY-CPP and the concomitant phenotypes to assess the suitability of this population for conducting a genome-wide QTL mapping study. Such efforts have been applied successfully toward other phenotypes associated with opioid addiction in mice, including liquid oral opioid consumption (Berrettini et al. 1994; Ferraro et al. 2005; Doyle et al. 2008) and opioid withdrawal (Kest et al. 2004, 2009). "
[Show abstract][Hide abstract] ABSTRACT: The rewarding property of opioids likely contributes to their abuse potential. Therefore, determining the genetic basis of opioid reward could aid in understanding the neurobiological mechanisms of opioid addiction, provided that it is a heritable trait. Here, we characterized the rewarding property of the widely abused prescription opioid oxycodone (OXY) in the conditioned place preference (CPP) assay using LG/J and SM/J parental inbred mouse strains and 17 parent-offspring families of a LG/J × SM/J F(47) /F(48) advanced intercross line (AIL). Following OXY training (5 mg/kg, i.p.), SM/J mice and AIL mice, but not LG/J mice, showed an increase in preference for the OXY-paired side, suggesting a genetic basis for OXY-CPP. SM/J mice showed greater locomotor activity than LG/J mice in response to both saline and OXY. LG/J, SM/J, and AIL mice all exhibited robust OXY-induced locomotor sensitization. Narrow-sense heritability (h(2) ) estimates of the phenotypes using linear regression and maximum likelihood estimation showed good agreement (r = 0.91). OXY-CPP was clearly not a heritable trait whereas drug-free- and OXY-induced locomotor activity and sensitization were significantly and sometimes highly heritable (h(2) = 0.30-0.84). Interestingly, the number of transitions between the saline- and OXY-paired sides emerged as a reliably heritable trait following OXY training (h(2) = 0.46-0.66) and could represent a genetic component of drug-seeking behavior. Thus, although OXY-CPP does not appear to be amenable to genome-wide quantitative trait locus mapping, this protocol will be useful for mapping other traits potentially relevant to opioid abuse.
"While the initial animals were developed on a mixed 129S6 × C57BL/6J background, the proximity of the KEPI gene to Oprm1 lead us to consider possible effects of " hitch-hiking " genes from the 129S6 genetic background, including Oprm1 (Gerlai, 1996). Oprm1 variants provide a major contribution to a quantitative trait locus (QTL) that influences morphine antinociception and selfadministration (Berrettini et al., 1994, Belknap et al., 1995, Bergeson et al., 2001). We thus identified recombinant KO animals with C57BL/6 markers in the appropriate genomic region by analyzing single nucleotide polymorphisms (SNPs) in and near the Oprm1 locus. "
[Show abstract][Hide abstract] ABSTRACT: We previously identified KEPI as a morphine-regulated gene using subtractive hybridization and differential display PCR. Upon phosphorylation by protein kinase C, KEPI becomes a powerful inhibitor of protein phosphatase 1. To gain insights into KEPI functions, we created KEPI knockout (KO) mice on mixed 129S6xC57BL/6 genetic backgrounds. KEPI maps onto mouse chromosome 10 close to the locus that contains the mu-opioid receptor (Oprm1) and provides a major quantitative trait locus for morphine effects. Analysis of single nucleotide polymorphisms in and near the Oprm1 locus identified a doubly-recombinant mouse with C57BL/6 markers within 1 Mb on either side of the KEPI deletion. This strategy minimized the amount of 129S6 DNA surrounding the transgene and documented the C57BL/6 origin of the Oprm1 gene in this founder and its offspring. Recombinant KEPIKO mice displayed (a) normal analgesic responses and normal locomotion after initial morphine treatments, (b) accelerated development of tolerance to analgesic effects of morphine, (c) elevated activity of protein phosphatase 1 in thalamus, (d) attenuated morphine reward as assessed by conditioned place preference. These data support roles for KEPI action in adaptive responses to repeated administration of morphine that include analgesic tolerance and drug reward.
"This gene shows a divergence between B6 and 129 strains in the intronic sequences surrounding exons 2 and 3, which may regulate transcript stability and C-terminal splicing (Zhou et al., 2001). Another of the quantitative trait loci discovered in this study was on chromosome 6, in the region of the gene encoding the NK1 receptor (Berrettini et al., 1994). In another study, Dockstader & van der Kooy (2001) observed that the absence of place preference to morphine in 129 ⁄ sv mice could be overcome by administration of a priming injection of morphine or an anxiolytic drug such as diazepam. "
[Show abstract][Hide abstract] ABSTRACT: Genetic background affects animal phenotype and therefore is of particular relevance to studies using genetically manipulated mice. Strain differences in hypothalamic-pituitary-adrenocortical (HPA) axis activity may contribute to background-specificity of some mutations. Here, we analysed components of the HPA axis in mice lacking a functional neurokinin-1 receptor (NK1-/-) on two backgrounds: backcrossed C57BL/6 (B6) and mixed C57BL/6 x 129/sv (129B6). We hypothesized that HPA axis activity would vary between these strains, leading to differences in the NK1-/- phenotype. We compared levels of plasma corticosterone between the groups, and found 129B6 mice exhibited elevated levels of stress-induced corticosterone compared with B6 mice, regardless of genotype. Although the level of basal corticotrophin-releasing factor and stress-induced c-fos mRNAs did not differ between the genotypes of either strain, examination of glucocorticoid receptor immunoreactivity within the hippocampus revealed that NK1-/- mice on the 129B6 background had elevated expression compared with wild-type, whilst there was no difference between genotypes in the B6 strain. Similarly, hippocampal neurogenesis in NK1-/- mice was greater than in wild-type on the 129B6 strain, and did not differ between genotypes on the B6 background. Finally, novelty- and morphine-induced locomotion were assessed. NK1-/- mice on the 129B6 background exhibited hyperlocomotion in response to novelty and greater sensitivity to the locomotor-stimulating properties of morphine than wild-type. In contrast, in B6 mice, no differences were observed between genotypes for either locomotor behaviour. In summary, we find that HPA axis activity differs between the strains and that there are profoundly background-specific effects of the NK1 receptor mutation.
European Journal of Neuroscience 03/2008; 27(3):683-90. DOI:10.1111/j.1460-9568.2008.06043.x · 3.18 Impact Factor
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