Genetic background influences the behavioural and molecular consequences of neurokinin‐1 receptor knockout

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 × 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.