Impact of tobacco flavoring on oral nicotine consumption in C57BL/6J mice.

BACKGROUND: The continued use of flavors in tobacco products has been a prominent factor in their popularity, yet little is known regarding their role in nicotine dependence. This study aimed to investigate the impact of tobacco flavoring on oral nicotine consumption in mice using the two-bottle choice (2BC) test and assessed the potential impact of age and sex in their interactions. METHODS: Adolescent and adult male and female C57BL/6J mice were used. First, voluntary consumption of tobacco flavor concentrate from a commercial electronic cigarette liquid vendor (Avail Vapor LLC) was measured; then, the effects of tobacco flavoring in combination with nicotine were examined. In one approach, tobacco flavor concentration was kept constant while nicotine concentration varied, and in the second, nicotine was kept constant while the tobacco flavor concentration varied. RESULTS: Overall, tobacco flavoring decreased oral nicotine consumption in mice, and its effects were sex- and age-dependent. Although females consumed the tobacco-flavored solution at a slightly higher rate than males, male mice were more sensitive to the effects of the combination (nicotine + tobacco). Furthermore, adolescent mice showed a starker reduction in nicotine consumption in the presence of tobacco flavoring compared to adult mice. This attenuation was most likely due to a basal aversion to the tobacco flavoring itself, thus, creating a negative synergistic effect with nicotine. CONCLUSIONS: Tobacco flavoring increases aversion to nicotine in the 2BC test in C57BL6J mice, suggesting that some flavors may diminish rather than enhance oral nicotine consumption in rodents.

Persistent sensory changes and sex differences in transgenic mice conditionally expressing HIV-1 Tat regulatory protein.

HIV-associated sensory neuropathies (HIV-SN) are prevalent in >50% of patients aged over 45 years many of which report moderate to severe chronic pain. Previous preclinical studies have investigated the mechanisms by which HIV-1 causes sensory neuropathies and pain-like behaviors. The aim of the present study is to delineate the role of chronic HIV-1 trans-activator of transcription protein (Tat) exposure in the development of neuropathy in mice. The temporal effects of conditional Tat expression on the development of hypersensitivity to mechanical (von Frey filaments) and thermal (heat or cold) stimuli were tested in male and female mice that transgenically expressed HIV-1 Tat in a doxycycline-inducible manner. Inducing Tat expression produced an allodynic response to mechanical or cold (but not heat) stimuli that respectively persisted for at least 23-weeks (mechanical hypersensitivity) or at least 8-weeks (cold hypersensitivity). Both allodynic states were greater in magnitude among females, compared to males, and mechanical increased hypersensitivity progressively in females over time. Acute morphine or gabapentin treatment partly attenuated allodynia in males, but not females. Irrespective of sex, Tat reduced intraepidermal nerve fiber density, the mean amplitude of sensory nerve action potentials (but not conductance), engagement in some pain-related ethological behaviors (cage-hanging and rearing), and down-regulated PPAR-α gene expression in lumbar spinal cord while upregulating TNF-α expression in dorsal root ganglion. Taken together, these data reveal fundamental sex differences in mechanical and cold hypersensitivity in response to Tat and demonstrate the intractable nature in female mice to current therapeutics. Understanding the role of Tat in these pathologies may aid the design of future therapies aimed at mitigating the peripheral sensory neuropathies that accompany neuroHIV.

Genotypic Differences in the Effects of Menthol on Nicotine Intake and Preference in Mice.

Menthol has been shown to exacerbate elements of nicotine addiction in humans and rodents; however, the mechanisms mediating its effects are not fully understood. This study examined the impact of genetic factors in menthol's effects on oral nicotine consumption by comparing two inbred mouse strains with differing sensitivities to nicotine. C57BL/6J (B6J) mice are nicotine-preferring, while DBA/2J (D2J) mice are not. While the effects of menthol on oral nicotine consumption have been highlighted in B6J mice, it is unknown if they extend to the D2J strain as well. Consequently, adolescent (PND 21) and adult (PND 63), male and female D2J mice were subjected to the nicotine two-bottle choice (2BC) paradigm with orally and systemically administered menthol. Then, we evaluated its impact on nicotine pharmacological responses in conditioned reward and nociception after systemic administration and, lastly, investigated the potential involvement of the TAAR1 gene and α7 nAChRs in menthol's effects. Menthol failed to enhance oral nicotine consumption in adult and adolescent female and male D2J mice. Moreover, this lack in effect was not due to nicotine concentration, oral aversion to menthol, or basal preference for nicotine. Menthol also failed to augment nicotine reward or enhance nicotine-induced antinociception in D2J mice, demonstrating that genetic background plays a significant role in sensitivity to menthol's effects on nicotine. Furthermore, TAAR1 or α7 nAChRs did not seem to mediate menthol's differential effects in D2J mice. These findings support the existence of genotype-specific mechanisms that may contribute to the variable effects of menthol in different populations.