Genetic Modifiers of Oral Nicotine Consumption in Null Mutant Mice.

The gene is strongly associated with the level of nicotine consumption in humans and manipulation of the expression or function of similarly alters nicotine consumption in rodents. In both humans and rodents, reduced or complete loss of function of leads to increased nicotine consumption. However, the mechanism through which decreased function of increases nicotine intake is not well-understood. Toward a better understanding of how loss of function of increases nicotine consumption, we have initiated efforts to identify genetic modifiers of deletion-dependent oral nicotine consumption in mice. For this, we introgressed the knockout (KO) mutation onto a panel of C57BL/6J-Chr#/NAJ chromosome substitution strains (CSS) and measured oral nicotine consumption in 18 CSS and C57BL/6 (B6) mice homozygous for the KO allele as well as their wild type littermates. As expected, nicotine consumption was significantly increased in KO mice relative to wildtype mice on a B6 background. Among the CSS homozygous for the KO allele, several exhibited altered nicotine consumption relative to B6 KO mice. Sex-independent modifiers were detected in CSS possessing A/J chromosomes 5 and 11 and a male-specific modifier was found on chromosome 15. In all cases nicotine consumption was reduced in the CSS KO mice relative to B6 KO mice and consumption in the CSS KO mice was indistinguishable from their wild type littermates. Nicotine consumption was also reduced in both KO and wildtype CSS mice possessing A/J chromosome 1 and increased in both KO and wild type chromosome 17 CSS relative to KO and wild type B6 mice. These results demonstrate the presence of several genetic modifiers of nicotine consumption in KO mice as well as identify loci that may affect nicotine consumption independent of genotype. Identification of the genes that underlie the altered nicotine consumption may provide novel insight into the mechanism through which deletion increases nicotine consumption and, more generally, a better appreciation of the neurobiology of nicotine intake.