McCutcheon, J.E.; (2007) Genetic background influences the effect of neurokinin-1 receptor "knockout" in the mouse. Doctoral thesis , University of London.

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Abstract

Strains of mice used in laboratory research differ markedly at a molecular, anatomical and behavioural level. Genetic manipulation in mice has become a widely used tool for the selective study of single genes and has also produced a great diversity of phenotypes. However, the interaction between manipulated genes and background strain has been less well examined. Here, the effect of neurokinin-1 (NK1) receptor disruption is shown to depend heavily on the genetic background of the mouse that it is studied in. NK1_/_ mice have previously been shown to display an anxiolytic and antidepressant-like phenotype, as well as having reduced sensitivity to the rewarding properties of the opiates. Here, after being transferred onto a C57BL/6 (B6) background, the anxiolytic effect of the mutation is lost, as is the differential response to morphine's locomotor stimulating properties. When the mutation is transferred onto a mixed C57BL/6 x 129/sv (B6:129) background the NK1 /_ mouse becomes more sensitive to morphine than wildtype counterparts, although no difference in anxiolysis is evident between the genotypes. Examination of the HPA axis in these animals revealed that B6:129 animals had higher levels of stress-induced corticosterone release than B6. Furthermore, NK1 /_ animals on the B6:129 background expressed higher levels of hippocampal glucocorticoid receptor and exhibited more neurogenesis in the hippocampus than wildtype. No differences in these parameters were observed for the genotypes in the B6 strain. Comparison of CRF and cFos mRNAs did not reveal any differences between genotypes in either strain. These results show that there are important epistatic interactions between genetic background and the NK1 receptor. These findings may be relevant for the treatment of anxiety disorders and opiate addiction in the genetically heterogeneous patient population.

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