Nicotine is largely responsible for the initiation and maintenance of tobacco dependence and contributes to a global health problem.
Aims:
This study characterizes nicotine oral consumption and preference in male and female mice of several Diversity Outbred (DO) founder strains: C57BL/6J, A/J, 129S1/SvImJ, PWK/PhJ, NOD/ShiLtJ, and CAST/EiJ. It assesses the impact of nicotine concentration on intake and preference, the potential interaction of strain with sex, and estimates the degree of heritable variation in nicotine consumption.
Methods:
Two-bottle choice oral self-administration paradigm was used to assess nicotine intake, nicotine preference, and total fluid intake in male and female mice of each strain in a concentration-response manner. A conditioned place preference (CPP) test was performed to evaluate the rewarding and aversive effects of nicotine in certain strains after systemic administration of the drug.
Results:
The highest nicotine-consuming strain was found to be 129S1/SvlmJ, and the lowest nicotine-consuming strain was A/J. Strain differences in nicotine intake were not due to differences in bitter and sweet tastes as shown in the saccharine and quinine two-bottle choice tests. A/J strain showed no significant CPP for nicotine while the 129S1/SvImJ strain showed a significant CPP for nicotine and a higher preference when compared to the C57BL/6J strain. Heritability estimates of nicotine intake were sex dependent and concentration dependent.
Conclusions:
Data support that nicotine consumption patterns are heritable with an influence of genotype in a voluntary oral self-administration paradigm. Results pave the way for future studies with the highly recombinant DO mice that might lead to the identification of novel genetic loci and genes influencing nicotine consumption.
AkinolaLSRahmanYOndoO, et al. (2022) Genotypic differences in the effects of menthol on nicotine intake and preference in mice. Front Neurosci16: 905330.
2.
AschhoffSSchroffKCWildenauerDB, et al. (2000) Nicotine consumption of several mouse strains using a two bottle choice paradigm. J Exp Animal Sci40: 171–177.
3.
AylorDLValdarWFoulds-MathesW, et al. (2011) Genetic analysis of complex traits in the emerging collaborative cross. Gen Res21: 1213–1222.
4.
BagdasDDiesterCMRileyJ, et al. (2019) Assessing nicotine dependence using an oral nicotine free-choice paradigm in mice. Neuropharmacology157: 107669.
5.
BagleyJRBaileyLSGagnonLH, et al. (2022) Behavioral phenotypes revealed during reversal learning are linked with novel genetic loci in diversity outbred mice. Add Neurosci4: 100045.
6.
BagleyJRCheslerEJPhilipVM, et al. (2021) Heritability of ethanol consumption and pharmacokinetics in a genetically diverse panel of collaborative cross mouse strains and their inbred founders. Alcohol Clin Exp Res45: 697–708.
7.
BeckerJBChartoffE (2019) Sex differences in neural mechanisms mediating reward and addiction. Neuropsychopharmacology44: 166–183.
8.
BelknapJKCrabbeJCYoungER (1993) Voluntary consumption of ethanol in 15 inbred mouse strains. Psychopharmacology112: 503–510.
9.
BryantCDBagdasDGoldbergLR, et al. (2019) C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception. Mol Pain15: 1744806918825046.
10.
CarstensECarstensMI (2022) Sensory effects of nicotine and tobacco. Nicotine Tob Res24: 306–315.
11.
D’SouzaMSMarkouA (2011) Neuronal mechanisms underlying development of nicotine dependence: Implications for novel smoking-cessation treatments. Addict Sci Clin Pract6: 4–16.
GlattARDentonKBoughterJDJr (2009) Variation in nicotine consumption in inbred mice is not linked to orosensory ability. Chem Senses34: 27–35.
15.
GoldbergLRKutluMGZeidD, et al. (2021) Systems genetic analysis of nicotine withdrawal deficits in hippocampus-dependent learning. Genes Brain Behav Advance online publication. DOI: 10.1111/gbb.12734.
16.
GoldmanDOrosziGDucciF (2005) The genetics of addictions: Uncovering the genes. Nat Rev Genet6: 521–532.
17.
GyekisJPDingmanMARevitskyAR, et al. (2012) Gustatory, trigeminal, and olfactory aspects of nicotine intake in three mouse strains. Behav Genet42: 820–829.
18.
KeaneTMGoodstadtLDanecekP, et al. (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature477: 289–294.
19.
KendlerKSSchmittEAggenSH, et al. (2008) Genetic and environmental influences on alcohol, caffeine, cannabis, and nicotine use from early adolescence to middle adulthood. Arch Gen Psychiatry65: 674–682.
20.
KlugeRScherneckSSchürmannA, et al. (2012) Pathophysiology and genetics of obesity and diabetes in the New Zealand obese mouse: A model of the human metabolic syndrome. Methods Mol Biol933: 59–73.
21.
KollmusHFuchsHLenggerC, et al. (2020) A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes. Mammal Gen31: 30–48.
22.
KotaDMartinBRRobinsonSE, et al. (2007) Nicotine dependence and reward differ between adolescent and adult male mice. J Pharmacol Exp Therap322: 399–407.
23.
LeADLiZFunkD, et al. (2006) Increased vulnerability to nicotine self-administration and relapse in alcohol-naive offspring of rats selectively bred for high alcohol intake. J Neurosci26: 1872–1879.
24.
Le FollBPiperMEFowlerCD, et al. (2022) Tobacco and nicotine use. Nat Rev Dis Prim8: 19.
25.
LiLJiaKZhouX, et al. (2013) Impact of nicotine metabolism on nicotine’s pharmacological effects and behavioral responses: Insights from a Cyp2a(4/5)bgs-null mouse. J Pharmacol Exp Therap347: 746–754.
26.
LiuMJiangYWedowR, et al. (2019) Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Gen51: 237–244.
27.
MeliaTWaxmanDJ (2020) Genetic factors contributing to extensive variability of sex-specific hepatic gene expression in diversity outbred mice. PLoS One15: e0242665.
28.
MeliskaCJBartkeAMcGlackenG, et al. (1995) Ethanol, nicotine, amphetamine, and aspartame consumption and preferences in C57BL/6 and DBA/2 mice. Pharmacol Biochem Behav50: 619–626.
29.
MillerCNKamensHM (2020) The role of nicotinic acetylcholine receptors in alcohol-related behaviors. Brain Res Bull163: 135–142.
30.
MogilJSWilsonSGBonK, et al. (1999) Heritability of nociception I: Responses of 11 inbred mouse strains on 12 measures of nociception. Pain80: 67–82.
31.
Mouse Genome Database (MGD)At the Mouse Genome Informatics website, The Jackson Laboratory, Bar Harbor, Maine. http://www.informatics.jax.org (accessed November 2021).
32.
NesilTKanitLCollinsAC, et al. (2011) Individual differences in oral nicotine intake in rats. Neuropharmacology61: 189–201.
33.
PekonenKKarlssonCLaaksoI, et al. (1993) Plasma nicotine and cotinine concentrations in mice after chronic oral nicotine administration and challenge doses. Eur J Pharmac Sci1: 13–18.
34.
PoçaKSParenteTEChagasLF, et al. (2017) Interstrain differences in the expression and activity of Cyp2a5 in the mouse liver. BMC Res Notes10: 125.
35.
RosecransJAKaranLD (1993) Neurobehavioral mechanisms of nicotine action: Role in the initiation and maintenance of tobacco dependence. J Subst Abuse Treat10: 161–170.
36.
RowellPPHurstHEMarloweC, et al. (1983) Oral administration of nicotine: Its uptake and distribution after chronic administration to mice. J Pharmacol Methods9: 249–261.
37.
SacconeSFHinrichsALSacconeNL, et al. (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Human Mol Genet16: 36–49.
38.
SacconeNLSacconeSFHinrichsAL, et al. (2009) Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet150B: 453–466.
39.
SclafaniABahraniMZukermanS, et al. (2010) Stevia and saccharin preferences in rats and mice. Chem Senses35: 433–443.
40.
SeemillerLRGoldbergLRSmithPB, et al. (2022) Genetic differences in nicotine sensitivity and metabolism in C57BL/6J and NOD/ShiLtJ mouse strains. Neuropharmacology221: 109279.
41.
SiuECTyndaleRF (2007) Characterization and comparison of nicotine and cotinine metabolism in vitro and in vivo in DBA/2 and C57BL/6 mice. Mol Pharmacol71: 826–834.
42.
SmithMLMignognaKMRokitaJL, et al. (2023) Identification of candidate genes for nicotine withdrawal in C57BL/6J × DBA/2J recombinant inbred mice. Genes Brain Behav22: e12844.
43.
SvensonKLGattiDMValdarW, et al. (2012) High-resolution genetic mapping using the mouse diversity outbred population. Genetics190: 437–447.
44.
TodteKTselisNDadmarzM, et al. (2001) Effects of strain, behavior and age on the self-administration of ethanol, nicotine, cocaine and morphine by two rat strains. Neuropsychobiology44: 150–155.
45.
UhlGRDrgonTJohnsonC, et al. (2008) “Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice. Biochem Pharmacol75: 98–111.
46.
VinkJMWillemsenGBoomsmaDI (2005) Heritability of smoking initiation and nicotine dependence. Behav Genet35: 397–406.
47.
YangHWangJRDidionJP, et al. (2011) Subspecific origin and haplotype diversity in the laboratory mouse. Nat Genet43: 648–655.
