Why flavored vape products may be attractive: Green apple tobacco flavor elicits reward-related behavior, upregulates nAChRs on VTA dopamine neurons, and alters midbrain dopamine and GABA neuron function

Avelar, Alicia J.; Akers, Austin T.; Baumgard, Zachary J.; Cooper, Skylar Y.; Casinelli, Gabriella P.; Henderson, Brandon J.

doi:10.1016/j.neuropharm.2019.107729

Cited by 45 publications

(77 citation statements)

References 53 publications

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“…In mice lacking nAChR α7, this COL1A2 dysregulation was partially blocked, but still showed some up-regulation. As mentioned above, nicotine is not the only stimulus for nAChR α7, and PG alone may alter nicotinic receptors, is in agreement with our previous study [7,17]. Recently, Kicic et al reported that asthmatic epithelial cells were unable to synthesize fibronectin and thus had less ability in wound healing [51].…”

Section: Discussionsupporting

confidence: 91%

“…However, as one of the nAChR-agonists, nicotine could initiate receptor-related pathways, and nicotine aerosol inhalation also induce inflammation [8]. Other chemicals may induce activation of nAChRs, and they may also trigger feedback-loops, similar to flavoring chemicals [17][18][19]. Although the biological structure and function of nAChRs has been well studied, limited information exists on how nAChRs are affected during e-cig induced lung dysregulation processes.…”

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confidence: 99%

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E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor

Wang¹,

Sundar²,

Li³

et al. 2020

Preprint

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Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has conducted to understand the mechanism of toxicological and pulmonary effects of e-cigs. We hypothesized that sub-chronic exposure of e-cigs induced inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChR α7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial-cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lungs were collected for determination of inflammatory responses and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased the lung influx of macrophages and T-lymphocytes, and the levels of pro-inflammatory cytokines, while nAChR α7 knockdown blocked the inflammatory responses. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8, and MMP9, in both sex mice were altered at both protein and gene levels when WT mice were exposed to PG alone in a sex-dependent manner. Moreover, MMP12 increased significantly in male mice exposed to PG with or without nicotine in a nAChR α7 dependent manner.Additionally, the abundance of ECM proteins, such as collagen and fibronectin, was significantly altered after sub-chronic e-cig exposure with or without nicotine in a sex-dependent manner, but nAChR α7 independent manner. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChR α7 in a sexdependent manner. electronic cigarette aerosol and inhaled nicotine effects on periodontal and pulmonary tissues. Oral Dis 2017, 23:1052-1057. 3. Kaur G, Muthumalage T, Rahman I: Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and nontobacco products. Toxicol Lett 2018, 288:143-155.4.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor

Wang¹,

Sundar²,

Li³

et al. 2020

Preprint

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“…The observed increase in COL1A2 following e-cig with PG alone exposure in both male and female mice demonstrates the significant health risk imposed by PG alone, in addition to the risks associated with PG nicotine. As mentioned above, nicotine might not be the only target that can activate nAChR α7, and PG alone via other indirectly mechanisms could activate nicotinic receptors, which may be in agreement with our previous study [8,19]. It is well known that collagen and fibronectin are required when the wound healing process happens and delayed wound healing were observed when epithelial cells were unable to synthesize fibronectin [61].…”

Section: Discussionsupporting

confidence: 88%

E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor: Role of nAChR α7 in ACE2 Covid-19 receptor regulation

Wang

Sundar

et al. 2020

Preprint

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Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanism that mediate, toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChR α7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lungs tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased the inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased ACE2 Covid-19 receptor, whereas nAChR α7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8, and MMP9 were altered both at the protein and mRNA transcript levels in female and male, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChR α7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin significantly in a sex-dependent manner, but without the direct role of nAChR α7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChR α7 in a sex-dependent manner.

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“…VTA DA neurons have been widely studied in various drug-related experiments for nearly all drugs of abuse acts on VTA DA neurons to stimulate DA neurotransmission into the ventral striatum, or nucleus accumbens (NAc)—commonly known as the mesolimbic pathway [ 68 , 109 , 110 , 111 ]. Further, nicotine-induced activation of this pathway stimulates reward, as seen in conditioned place preference (CPP) assays [ 26 , 55 , 82 , 112 ]. Whereas, lesioning of this pathway completely abolishes nicotine reward-related behavior, nicotine self-administration, and nicotine-induced locomotion [ 85 , 113 , 114 ].…”

Section: Neurocircuitry Involved In Nicotine Addictionmentioning

confidence: 99%

“…These effects are due to menthol-induced nicotinic acetylcholine receptor (nAChR) upregulation [ 18 , 20 , 21 ], enhanced dopamine neuron excitability and dopamine release [ 22 , 23 ], and TrpM8-dependent mechanisms [ 24 ]. Based on a recent study reporting green apple and other fruity flavors to be the most popular of ENDS flavorants [ 9 , 25 ], additional reports have identified popular green apple flavorants, farnesol and farnesene, to not only enhance nicotine reward in a mouse model, but also display rewarding properties in the absence of nicotine [ 19 , 26 , 27 ]. These behavioral effects were found to be caused by changes in nAChR upregulation or stoichiometry, and ventral tegmental area dopamine neuron firing.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Electronic Nicotine Delivery System (ENDS) Flavors on Nicotinic Acetylcholine Receptors and Nicotine Addiction-Related Behaviors

Cooper

Henderson

2020

Molecules

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Over the past two decades, combustible cigarette smoking has slowly declined by nearly 11% in America; however, the use of electronic cigarettes has increased tremendously, including among adolescents. While nicotine is the main addictive component of tobacco products and a primary concern in electronic cigarettes, this is not the only constituent of concern. There is a growing market of flavored products and a growing use of zero-nicotine e-liquids among electronic cigarette users. Accordingly, there are few studies that examine the impact of flavors on health and behavior. Menthol has been studied most extensively due to its lone exception in combustible cigarettes. Thus, there is a broad understanding of the neurobiological effects that menthol plus nicotine has on the brain including enhancing nicotine reward, altering nicotinic acetylcholine receptor number and function, and altering midbrain neuron excitability. Although flavors other than menthol were banned from combustible cigarettes, over 15,000 flavorants are available for use in electronic cigarettes. This review seeks to summarize the current knowledge on nicotine addiction and the various brain regions and nicotinic acetylcholine receptor subtypes involved, as well as describe the most recent findings regarding menthol and green apple flavorants, and their roles in nicotine addiction and vaping-related behaviors.

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Why flavored vape products may be attractive: Green apple tobacco flavor elicits reward-related behavior, upregulates nAChRs on VTA dopamine neurons, and alters midbrain dopamine and GABA neuron function

Cited by 45 publications

References 53 publications

E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor

E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor

E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor: Role of nAChR α7 in ACE2 Covid-19 receptor regulation

The Impact of Electronic Nicotine Delivery System (ENDS) Flavors on Nicotinic Acetylcholine Receptors and Nicotine Addiction-Related Behaviors

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