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

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.

Polymorphic SNPs, short tandem repeats and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains

“…Mutations can be categorized into several classes: Single Nucleotide Polymorphisms (SNPs), Short Tandem Repeats (STRs), and Structural Variations (SVs). SNPs and SVs that differentiate C57BL/6J and C57BL/6N substrains have been previously reported (6)(7)(8)(9), whereas to our knowledge, genome wide STR polymorphisms have never been identified among C57BL substrains. STRs are highly variable elements that play a pivotal role in multiple genetic diseases, population genetics applications, and forensic casework.…”

“…Whole Genome Sequencing (WGS) technology provides a deep characterization of Single Nucleotide Polymorphisms (SNPs), small insertions and deletions (INDELs), Short Tandem Repeats (STRs), and Structural Variations (SVs). SNPs that differentiate a few of the C57BL/6 substrains have been previously reported 21,26 . While most SNPs are expected to have no functional consequences, a subset will; for example, SNPs in regulatory and coding regions, which can profoundly alter gene expression and function.…”

“…Numerous studies have reported phenotypic differences among various C57BL/6and C57BL/10-derived substrains, which are likely attributable to genetic variation. For C57BL/6 substrains, these differences include learning behavior 9 , prepulse inhibition 10 , anxiety and depression 11 , fear conditioning [12][13][14] , glucose tolerance 15 , alcohol-related behaviors 16,17 , and responses to other various drugs [18][19][20][21] . For C57BL/10 substrains, these differences include seizure traits 22 and responses to drugs 23 .…”

Ca2+ Imaging With Two-photon Microscopy to Detect the Disruption of Brain Function in Mice Administered With Neonicotinoid Insecticides

“…In addition, the effects of nicotine exposure on behavior vary, depending on the animal species, age, sex, strain, and dose 26, 34,35 . The subcutaneous injection of nicotine into adult male C57BL6/J mice signi cantly increases anxiety-like behavior at a dose of 0.05 mg/kg but not at a dose of 0.1 mg/kg or 0.25 mg/kg 9 . We observed no signi cant changes in the low concentration nicotine group (0.33 mg/kg bw, p.o.…”

“…Two-photon microscopy utilizes laser scanning, enabling the visualization of the function and construction of neurons in living awake animals. The somatosensory cortex is located in the anterior part of the parietal lobe and contributes to higher sensory functions by integrating signals received from sensory receptors and perceiving them as meaningful information 9,10 . The α4β2 and α7 subtypes are the commonly expressed nAChRs 10,11 .…”