CD-1 mice show individual differences in nicotine preference in a modified two-bottle oral self-administration model

Junran Cao

doi:10.3389/fpsyt.2012.00028

Abstract

Although both animal and human studies reveal significant contributions of genetics to smoking addiction, many human studies were underpowered or biased by potential confounding variables, and animal genetic studies are challenged by limited genetic variations and lack of convincing phenotypes. To address these concerns, we used non-sibling outbred CD-1 mice to evaluate individual differences in nicotine preference with a modified two-bottle oral self-administration model. Animals were first given free access to two bottles, one filled with nicotine dissolved in 2% saccharin and the other with saccharin only. Under this regular two-bottle choice condition, the majority of animals avoided the nicotine solution with limited individual differences. However, when we modified the model by introducing 4 days of exposure to 5% saccharin in the drinking water, the animals significantly increased nicotine consumption in the two-bottle choice test, with about 30% animals showing a nicotine preference. Nicotine preference after 5% saccharin treatment remained elevated throughout the 28 days of the experiment. Further, we found there existed striking individual differences in nicotine consumption after exposure to 5% saccharin, with a range of 0–100% of total liquid consumption. The enhanced individual differences and the ratio of nicotine consumption were observed at different concentrations of nicotine (10–80 μg/ml) and in both adolescents and adults. Further examination on the induction mechanism showed that the long-lasting nicotine preference was not correlated with nicotine consumption before the induction, 5% saccharin consumption, or weight gain during the induction. Although liquid consumption during the 4 days of 5% saccharin exposure was decreased by about 30%, comparable liquid restriction alone for 4 days did not induce nicotine preference. Together, this study showed a strong and stable nicotine preference in CD-1 mice, which was induced by a short-term high concentration of saccharin in the drinking water. Considering the nature and heterogeneity of CD-1 mice, the striking individual differences imply that genetics plays an important role in nicotine preference observed in these animals.

Highlights

Genetic epidemiologic studies have revealed moderate to high heritability for smoking-related behaviors (Li et al, 2003; Xian et al, 2003; Lessov et al, 2004; Ho and Tyndale, 2007)
EXPERIMENT 1: 5% SACCHARIN INDUCED NICOTINE PREFERENCE AND INCREASED INDIVIDUAL VARIATION IN NICOTINE CONSUMPTION Before 5% saccharin induction, the average consumption ratio of nicotine 10 μg/ml vs. total liquid was less than 40% (Figure 1A)
Genetic factors contribute to smoking addiction, which is reflected in individual differences in various smoking-related behaviors

Summary

Introduction

Genetic epidemiologic studies have revealed moderate to high heritability for smoking-related behaviors (Li et al, 2003; Xian et al, 2003; Lessov et al, 2004; Ho and Tyndale, 2007). The field is relatively lacking appropriate animal models that can compensate for potential confounding variables in human genetic studies. To identify susceptibility loci and genes for nicotine dependencerelated behaviors, a genetically variable population is preferred. The CD1 mouse is an outbred line derived from a colony of Swiss mice started in 1926 (Rice and O’Brien, 1980). They are readily available from vendors such as Charles River and Harlan. Similar work on smoking-related behaviors has not been reported

Methods

Results

Conclusion