Several caveats apply to studies of null mutant mice, including the fact that most gene-targeted mice, including those used in this study, are developed on a mixed genetic background, usually C57Bl/6J and a 129 substrain and these parental strains differ in responses to ethanol and many other drugs (Phillips et al., 1999). Four of the lines of knockout mice used in this study were backcrossed on the C57Bl/6J strain for many generations, reducing the potential confounding effects of the mixed genetic background, but genetic background may have a role in the phenotypes of Ctsf (−/−) and Il1rn (−/−) which were not backcrossed. Another concern is that homologous recombination places additional "hitchhiking" (e.g., 129 strain) DNA near the disrupted gene (Crusio, 1996; Gerlai, 1996). The complete replacement of 129 alleles is limited by the probability of recombination; even after 12 backcrosses a segment of 129-derived chromosome (about 16 centiMorgans) remains surrounding the mutated gene (Festing, 1992) and these neighboring genes can potentially influence the phenotype of the null mice. To distinguish the role of null genes and "hitchhiking" genes, it is
