The Impact of High or Low Doses of Nicotine in a Mouse Model of Vapor Self-Administration.

INTRODUCTION: A wide variety of nicotine concentrations and formulations are available to users of electronic nicotine delivery systems (ENDS). This is increasingly true when considering the many flavors available with ENDS products. To date, there have been few preclinical investigations into the impact of nicotine doses, with and without flavors, on vaping-related behaviors. This present study evaluated how nicotine concentrations relevant to tank-based and pod-based ENDS, with and without flavors, impact reinforcement-related behavior in a mouse model. AIMS AND METHODS: Adult male and female C57/BL6J mice were used in vapor-inhalation self-administration assays. Mice were assigned e-liquids containing 6 mg/mL or 60 mg/mL nicotine. Additional mice were assigned these nicotine doses with green apple or menthol flavorants. Mice were trained on fixed-ratio 1 for 10, 2-hour sessions, then five sessions at FR3, three progressive ratio sessions, and two FR3 sessions. RESULTS: We observed male mice exhibited higher reinforcement-related behavior to menthol-flavored 6 mg/mL nicotine when compared to female mice. Males were only observed to have a menthol-induced enhancement of self-administration at 6 mg/mL nicotine and not 60 mg/mL nicotine. However, female mice exhibited significant menthol-induced increases in reinforcement-related behaviors with 60 mg/mL nicotine. CONCLUSIONS: These data provide evidence that males and females exhibit different dose sensitivities to nicotine. These sex-dependent differences in nicotine sensitivity also indicate that flavor-induced enhancement in nicotine intake is dependent on the different doses for each sex. IMPLICATIONS: There has been much discussion recently regarding the impact of flavors on vaping-related behavior. Our current study may support prior investigations that suggest flavors enhance the palatability of nicotine-containing products. However, this current study provides evidence that males and females exhibit different sensitivities to nicotine.

Chemical Flavorants in Vaping Products Alter Neurobiology in a Sex-Dependent Manner to Promote Vaping-Related Behaviors.

Electronic nicotine delivery systems (ENDS) are distinctly different from combustible cigarettes because of the availability of flavor options. Subjective measures have been used to demonstrate that adults and adolescents prefer flavors for various reasons; (1) they are pleasing and (2) they mask the harshness of nicotine. Despite this, there have been few investigations into the molecular interactions that connect chemical flavorants to smoking or vaping-related behaviors. Here, we investigated the effects of three chemical flavorants (hexyl acetate, ethyl acetate, and methylbutyl acetate) that are found in green apple (GA) ENDS e-liquids but are also found in other flavor categories. We used a translationally relevant vapor self-administration mouse model and observed that adult male and female mice self-administered GA flavorants in the absence of nicotine. Using α4-mCherryα6-GFP nicotinic acetylcholine receptor (nAChR) mice, we observed that mice exposed to GA flavorants exhibited a sex-specific increase (upregulation) of nAChRs that was also brain-region specific. Electrophysiology revealed that mice exposed to GA flavorants exhibited enhanced firing of ventral tegmental area dopamine neurons. Fast-scan cyclic voltammetry revealed that electrically stimulated dopamine release in the nucleus accumbens core is increased in mice that are exposed to GA flavorants. These effects were similarly observed in the medial habenula. Overall, these findings demonstrate that ENDS flavors alone change neurobiology and may promote vaping-dependent behaviors in the absence of nicotine. Furthermore, the flavorant-induced changes in neurobiology parallel those caused by nicotine, which highlights the fact that nonmenthol flavorants may contribute to or enhance nicotine reward and reinforcement.SIGNIFICANCE STATEMENT The impact of flavors on vaping is a hotly debated topic; however, few investigations have examined this in a model that is relevant to vaping. Although a full understanding of the exact mechanism remains undetermined, our observations reveal that chemical flavorants in the absence of nicotine alter brain circuits relevant to vaping-related behavior. The fact that the flavorants investigated here exist in multiple flavor categories of vaping products highlights the fact that a multitude of flavored vaping products may pose a risk toward vaping-dependent behaviors even without the impact of nicotine. Furthermore, as the neurobiological changes have an impact on neurons of the reward system, there exists the possibility that nonmenthol flavorants may enhance nicotine reward and reinforcement.

Examining the role of acceptor molecule structure in self-assembled bilayers: surface loading, stability, energy transfer, and upconverted emission.

Self-assembly of sensitizer and acceptor molecules has recently emerged as a promising strategy to facilitate and harness photon upconversion via triplet-triplet annihilation (TTA-UC). In addition to the energetic requirements, the structure and relative orientation of these molecules can have a strong influence on TTA-UC rates and efficiency. Here we report the synthesis of five different acceptor molecules composed of an anthracene core functionalized with 9,10- or 2,6-phenyl, methyl, or directly bound phosphonic acid groups and their incorporation into self-assembled bilayers on a ZrO2 surface. All five films facilitate green-to-blue photon upconversion with Φuc as high as 0.0023. The efficiency of TTA, and not triplet energy transfer, fluorescence, or losses via FRET, was primarily responsible for dictating the Φuc emission. Even for molecules having similar photophysical properties, variation in the position of the phosphonic acid resulted in dramatically different ΦTTA, Ith values, γTTA, and D. Interestingly, we observed a strong linear correlation between ΦTTA and the Ith value but the cause of this relationship, if any, is unclear.

Multimolecular assemblies on high surface area metal oxides and their role in interfacial energy and electron transfer.

High surface area metal oxides offer a unique substrate for the assembly of multiple molecular components at an interface. The choice of molecules, metal oxide, and the nature of the assembly method can have a profound influence on the mechanism, rate, and efficiency of photoinduced energy and electron transfer events at the interface. Owing to their diversity and high level of control, these interfacial assemblies are of interest for numerous applications including solar energy conversion, photoelectrosynthesis, photo-writable memory, and more. Although these assemblies are generated with very different goals in mind, they rely on similar surface binding motifs and molecular structure-property relationships. Therefore, the goal of this review is to summarize the various strategies (i.e. co-deposition, axial coordination, metal ion linkages, electrostatics, host-guest interactions, etc.) for assembling chromophores, hosts, electron donors/acceptors, and insulating co-adsorbent molecules on mesoporous metal oxide substrates. The assembly, synthesis, and characterization, as well as subsequent photoinduced events (i.e. cross-surface energy/electron transfer, interchromophore energy transfer, electron injection, and others) are discussed for the various assembly strategies.

Coupling N-H Deprotonation, C-H Activation, and Oxidation: Metal-Free C(sp3)-H Aminations with Unprotected Anilines.

An intramolecular oxidative C(sp3)-H amination from unprotected anilines and C(sp3)-H bonds readily occurs under mild conditions using t-BuOK, molecular oxygen and N,N-dimethylformamide (DMF). Success of this process, which requires mildly acidic N-H bonds and an activated C(sp3)-H bond (BDE < 85 kcal/mol), stems from synergy between basic, radical, and oxidizing species working together to promote a coordinated sequence of deprotonation: H atom transfer and oxidation that forges a new C-N bond. This process is applicable for the synthesis of a wide variety of N-heterocycles, ranging from small molecules to extended aromatics without the need for transition metals or strong oxidants. Computational results reveal the mechanistic details and energy landscape for the sequence of individual steps that comprise this reaction cascade. The importance of base in this process stems from the much greater acidity of transition state and product for the 2c,3e C-N bond formation relative to the reactant. In this scenario, selective deprotonation provides the driving force for the process.

Harnessing Molecular Photon Upconversion in a Solar Cell at Sub-solar Irradiance: Role of the Redox Mediator.

Self-assembled bilayers offer a promising strategy to directly harness photon upconversion via triplet-triplet annihilation (TTA-UC) and increase maximum theoretical solar cell efficiencies from 33% to >43%. Here we demonstrate that the choice of redox mediator in these solar cells has a profound influence on both the light harvesting and TTA-UC efficiency. Devices with CoII/III(phen)3 as the redox mediator produced the highest photocurrent yet generated from TTA-UC (0.158 mA cm-2) under 1 sun. Despite generating less photocurrent, CoII/III(pz-py-pz)2 devices achieved maximum TTA-UC efficiency at excitation intensities well below solar irradiance (0.8 mW cm-2), which is on par with the lowest value yet reported for any TTA-UC system. The large variation in performance with respect to mediator is attributed to triplet excited-state quenching via (1) energy transfer or paramagnetic quenching by the CoII species and (2) excited-state electron transfer to CoIII species.

Double C-H amination by consecutive SET oxidations.

A new method for intramolecular C-H oxidative amination is based on a FeCl3-mediated oxidative reaction of anilines with activated sp(3) C-H bonds. The amino group plays multiple roles in the reaction cascade: (1) as the activating group in single-electron-transfer (SET) oxidation process, (2) as a directing group in benzylic/allylic C-H activation at a remote position, and (3) internal nucleophile trapping reactive intermediates formed from the C-H activation steps. These multielectron oxidation reactions proceed with catalytic amounts of Fe(iii) and inexpensive reagents.

Photon upconversion and photocurrent generation via self-assembly at organic-inorganic interfaces.

Molecular photon upconversion via triplet-triplet annihilation (TTA-UC), combining two or more low energy photons to generate a higher energy excited state, is an intriguing strategy to surpass the maximum efficiency for a single junction solar cell (<34%). Here, we introduce self-assembled bilayers on metal oxide surfaces as a strategy to facilitate TTA-UC emission and demonstrate direct charge separation of the upconverted state. A 3-fold enhancement in transient photocurrent is achieved at light intensities as low as two equivalent suns. This strategy is simple, modular and offers unprecedented geometric and spatial control of the donor-acceptor interactions at an interface. These results are a key stepping stone toward the realization of an efficient TTA-UC solar cell that can circumvent the Shockley-Queisser limit.