Author ORCID Identifier

https://orcid.org/0000-0003-0168-4515

Defense Date

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Mohamad Imad Damaj

Abstract

Although the detrimental effects of tobacco use have been expressed to the public for many years, many users still face immense difficulty quitting due to the addictive effects of nicotine. The use of flavor additives or ‘flavorants’ in tobacco products has contributed significantly to their continued popularity, engendering unprecedented levels of tobacco use globally. Substantial evidence indicates that in addition to increasing the appeal of tobacco products, certain flavorants may also exert potent pharmacological and toxicological effects beyond their function as odorants. The widespread availability of flavored tobacco products and their continued use thus pose a significant public health risk, yet their role in the maintenance of nicotine use is poorly understood. More importantly, factors such as sex, age, and genetic contributions remain unclear in the interaction of flavors in nicotine-containing products. This dissertation examined how commonly used flavorants (menthol and tobacco) impact nicotine self-administration using a two-pronged approach (oral vs. inhalation). Our central hypothesis was that, in general, flavors would enhance nicotine intake in a sex-, age-, and genotype-dependent manner. In the oral self-administration paradigm, we used the two-bottle choice (2BC) test to measure nicotine consumption and preference under various conditions. For the inhalation studies, we developed and characterized a novel mouse model of nicotine vapor self-administration. The research presented herein demonstrates that menthol indeed does not play an inert role, but actively facilitates oral and inhaled nicotine self-administration. Moreover, we demonstrate clear influences of age, sex, and genotype in its effects. Menthol enhanced oral, systemic, and inhaled nicotine intake in a sex-, age- and genotype-dependent manner. Orally and systemically administered menthol enhanced nicotine intake and preference in male and female C57BL/6J (B6J) mice but not in adult or adolescent male or female DBA/2J (D2J) mice. Menthol also enhanced nicotine vapor self-administration in only female B6J mice; however, we are yet to test its effects in D2J mice. Further, its effects in B6J mice suggested the involvement of orosensory-dependent and -independent mechanisms. We also uncovered a role for the α5 nicotinic subunit in regulating oral menthol consumption and identified it as a potential target in understanding the biological mechanisms underlying menthol’s effects. Lastly, we report that the route of administration impacts the effects of tobacco flavoring in mice. Although tobacco flavoring failed to enhance oral or inhaled nicotine self-administration, it enhanced responding for nicotine-free tobacco-flavored vapor in female but not male mice, whereas it had no effect in the oral self-administration paradigm.

Rights

© Lois Setemi Akinola

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-12-2022

Available for download on Wednesday, August 11, 2027

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