Abstract
The gene CHRNA5 is strongly associated with the level of nicotine consumption in humans and manipulation of the expression or function of Chrna5 similarly alters nicotine consumption in rodents. In both humans and rodents, reduced or complete loss of function of Chrna5 leads to increased nicotine consumption. However, the mechanism through which decreased function of Chrna5 increases nicotine intake is not well-understood. Toward a better understanding of how loss of function of Chrna5 increases nicotine consumption, we have initiated efforts to identify genetic modifiers of Chrna5 deletion-dependent oral nicotine consumption in mice. For this, we introgressed the Chrna5 knockout (KO) mutation onto a panel of C57BL/6J-Chr#A/J/NAJ chromosome substitution strains (CSS) and measured oral nicotine consumption in 18 CSS and C57BL/6 (B6) mice homozygous for the Chrna5 KO allele as well as their Chrna5 wild type littermates. As expected, nicotine consumption was significantly increased in Chrna5 KO mice relative to Chrna5 wildtype mice on a B6 background. Among the CSS homozygous for the Chrna5 KO allele, several exhibited altered nicotine consumption relative to B6 Chrna5 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 Chrna5 KO mice relative to B6 Chrna5 KO mice and consumption in the CSS KO mice was indistinguishable from their wild type littermates. Nicotine consumption was also reduced in both Chrna5 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 Chrna5 KO mice as well as identify loci that may affect nicotine consumption independent of Chrna5 genotype. Identification of the genes that underlie the altered nicotine consumption may provide novel insight into the mechanism through which Chrna5 deletion increases nicotine consumption and, more generally, a better appreciation of the neurobiology of nicotine intake.
Highlights
It has become evident that nicotinic acetylcholine receptors that contain the α5 subunit play a critical role in the risk for nicotine dependence
In order to screen for potential genetic modifiers that alter the effect of Chrna5 deletion on oral nicotine intake, the Chrna5 null mutation was introgressed onto a panel of 20 background strain is C57BL/6J (B6) x A/J chromosome substitution strains (CSS) [20, 23] as described in the methods
Because the most common measure used to assess oral nicotine intake is dose and dose is dependent upon the amount of fluid intake as well as the weight of the mice, the CSS panel was assessed for whether there was a main effect of strain on either fluid intake or animal body weight across the study
Summary
It has become evident that nicotinic acetylcholine receptors (nAChRs) that contain the α5 subunit play a critical role in the risk for nicotine dependence. Human studies repeatedly have found an association between genetic variants in CHRNA5, the gene that codes for the nAChR α5 subunit, nicotine dependence and other nicotine dependence relevant phenotypes [1,2,3,4,5,6,7]. A few early studies demonstrated that Chrna played a role in sensitivity to the acute effects on nicotine in mice [8, 9]. More recent studies using rodent models have provided further insight into the role of Chrna in nicotine dependence. Fowler et al [10] found that Chrna knockout (KO) mice, unlike wildtype controls, did not reduce their responding for i.v. nicotine selfadministration as the unit dose increased. At the highest nicotine dose tested, Chrna KO mice self-administered five times more nicotine than did their wildtype controls. Jackson et al [11] reported that Chrna KO mice exhibited conditioned place preference at higher doses of nicotine than did wildtype controls and Wilking and Stitzel [12] as well as Bagdas et al [13] showed that Chrna KO mice consume more nicotine via oral administration, especially at higher nicotine concentrations, relative to wildtype littermates
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