C57BL/6 Substrain Differences in Pharmacological Effects after Acute and Repeated Nicotine Administration.

Lois S Akinola,Andy Z X Zhu,Bryan Mckiver,Rachel F Tyndale,Wisam Toma,M Imad Damaj,Vivek Kumar

doi:10.3390/brainsci9100244

Abstract

Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially elucidate the novel genes and/or gene networks regulating various aspects of nicotine dependence. Using the closely related C57BL/6 (B6) mice substrains, recent reports have noted phenotypic differences within C57BL/6J (B6J) and C57BL/6N (B6N) mice for some drugs of abuse: alcohol, opiates, and cocaine. However, the differences in nicotine’s effects have not yet been described in these substrains. We examined the phenotypic differences in these substrains following the acute and repeated administration of nicotine in several pharmacological measures, including locomotion (after acute and repeated exposure), body temperature, nociception, and anxiety-like behaviors. We report substrain differences in the pharmacological effects of acute and repeated nicotine administration in the B6 substrains. Overall, we show enhanced nicotine sensitivity to locomotion, hypothermia, antinociception, and anxiety-like behaviors in the B6J mouse substrain compared to B6N. In the repeated administration paradigm, both the B6N and B6J substrains showed no sensitized locomotor responses after repeated exposure to nicotine at the two doses tested. This study thus provides evidence that the B6 mouse substrains may be useful for genetic studies to elucidate some of the genetic variants involved in tobacco dependence and addiction.

Highlights

The World Health Organization (WHO) reports more than seven million deaths each year from direct tobacco use, which is estimated to rise to 10 million deaths per year by the year 2030 [1,2,3]
We investigated the effects of acute nicotine administration on thermal antinociception, locomotor activity, and body temperature
Nicotine produced a dose-responsive increase in the tail-flick latency (Figure 1A) in the B6J and between the C57BL/6N (B6N) substrains with an ED50 (±confidence limits (CL)) of 1.3 (0.56–1.89) and 5.9 (3.1–11.23) mg/kg, respectively (Table 1)

Summary

Introduction

The World Health Organization (WHO) reports more than seven million deaths each year from direct tobacco use, which is estimated to rise to 10 million deaths per year by the year 2030 [1,2,3]. Several nicotinic receptor gene variants have been implicated in nicotine dependence (CHRNA5-CHRNA3-CHRNB4 within the q25.1 region of chromosome 15, as well as in the primary metabolism gene, CYP2A6) These genetic variants explain only a small proportion of the genetic risk of tobacco-use initiation and dependence [9,10,11]. A discovery-based approach to genetic mapping known as “Quantitative trait locus (QTL) mapping” has been successfully used in the identification of genetic variants underlying several complex phenotypes [13,14] This approach allows the mapping of regions of polymorphism within the genome to narrow intervals, facilitating the identification of causative variants associated with complex behaviors.

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