This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and ...intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and α3- and α4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with α3- and α4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3 mg/kg). CB2KO mice did not show nicotine-induced place conditioning and self-administered significantly less nicotine. In addition, AM630 was able to block (3 mg/kg) nicotine-induced CPP and reduce (1 and 3 mg/kg) nicotine self-administration. Under baseline conditions, TH, α3-nAChR, and α4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with α3- and α4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence.
Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine and that a large proportion of smokers eventually become dependent on ...nicotine. In humans, nicotine acutely produces positive reinforcing effects, including mild euphoria, whereas a nicotine abstinence syndrome with both somatic and affective components is observed after chronic nicotine exposure. Animal models of nicotine self-administration and chronic exposure to nicotine have been critical in unveiling the neurobiological substrates that mediate the acute reinforcing effects of nicotine and emergence of a withdrawal syndrome during abstinence. However, important aspects of the transition from nicotine abuse to nicotine dependence, such as the emergence of increased motivation and compulsive nicotine intake following repeated exposure to the drug, have only recently begun to be modeled in animals. Thus, the neurobiological mechanisms that are involved in these important aspects of nicotine addiction remain largely unknown. In this review, we describe the different animal models available to date and discuss recent advances in animal models of nicotine exposure and nicotine dependence. This review demonstrates that novel animal models of nicotine vapor exposure and escalation of nicotine intake provide a unique opportunity to investigate the neurobiological effects of second-hand nicotine exposure, electronic cigarette use, and the mechanisms that underlie the transition from nicotine use to compulsive nicotine intake.
Rationale
Electronic cigarettes are becoming increasingly popular among smokers worldwide. Commonly reported reasons for use include the following: to quit smoking, to avoid relapse, to reduce urge ...to smoke, or as a perceived lower-risk alternative to smoking. Few studies, however, have explored whether electronic cigarettes (e-cigarettes) deliver measurable levels of nicotine to the blood.
Objective
This study aims to explore in experienced users the effect of using an 18-mg/ml nicotine first-generation e-cigarette on blood nicotine, tobacco withdrawal symptoms, and urge to smoke.
Methods
Fourteen regular e-cigarette users (three females), who are abstinent from smoking and e-cigarette use for 12 h, each completed a 2.5 h testing session. Blood was sampled, and questionnaires were completed (tobacco-related withdrawal symptoms, urge to smoke, positive and negative subjective effects) at four stages: baseline, 10 puffs, 60 min of ad lib use and a 60-min rest period.
Results
Complete sets of blood were obtained from seven participants. Plasma nicotine concentration rose significantly from a mean of 0.74 ng/ml at baseline to 6.77 ng/ml 10 min after 10 puffs, reaching a mean maximum of 13.91 ng/ml by the end of the ad lib puffing period. Tobacco-related withdrawal symptoms and urge to smoke were significantly reduced; direct positive effects were strongly endorsed, and there was very low reporting of adverse effects.
Conclusions
These findings demonstrate reliable blood nicotine delivery after the acute use of this brand/model of e-cigarette in a sample of regular users. Future studies might usefully quantify nicotine delivery in relation to inhalation technique and the relationship with successful smoking cessation/harm reduction.
The introduction of a new product line of the popular disposable electronic cigarette brand Puffbar, advertised as containing synthetic nicotine, has drawn attention to the increasing use of ...synthetic nicotine in marketed products and its uncertain regulatory status. A search of the Truth Tobacco Industry Documents revealed that the industry considered using synthetic nicotine already in the 1960s, efforts that were abandoned due to high costs and insufficient purity. Recent patents revealed renewed efforts to develop more efficient strategies for the synthesis of nicotine. Nicotine exists as two stereoisomers,
-nicotine and
-nicotine. While
-nicotine is the prevalent (>99%) form of nicotine in tobacco, a market-leading form of synthetic nicotine contains both stereoisomers at equal amounts, raising concerns about inaccurate labelling and the poorly understood health effects of
-nicotine. Other manufacturers, including a leading vendor of pharmaceutical grade nicotine, developed stereospecific strategies to synthesise pure
-nicotine, now added to electronic cigarette products marketed in the USA and UK. While
-nicotine and
-nicotine can be differentiated by enantioselective High Performance Liquid Chromatography (HPLC), differentiation of synthetic (fossil-derived) from tobacco-derived
-nicotine will require development of methods to measure carbon isotope (
C or
C) content. Vendors claim that the FDA has no authority to regulate synthetic nicotine as a tobacco product, allowing them to circumvent the premarket tobacco product application process. However, legal analysis suggests that FDA may have the authority to regulate synthetic nicotine as a drug. Alternatively, Congress needs to include nicotine from any source within the legal definition of tobacco products.
Aims
To measure the systemic retention of nicotine, propylene glycol (PG) and vegetable glycerin (VG) in electronic cigarette (e‐cigarette) users, and assess the abuse liability of e‐cigarettes by ...characterizing nicotine pharmacokinetics.
Design
E‐cigarette users recruited over the internet participated in a 1‐day research ward study. Subjects took 15 puffs from their usual brand of e‐cigarette. Exhaled breath was trapped in gas‐washing bottles and blood was sampled before and several times after use.
Setting
San Francisco, California, USA.
Participants
Thirteen healthy, experienced adult e‐cigarette users (six females and seven males).
Measurements
Plasma nicotine was analyzed by gas chromatography–mass spectrometry (GC‐MS/MS) and nicotine, VG and PG in e‐liquids and gas traps were analyzed by LC‐MS/MS. Heart rate changes and subjective effects were assessed.
Findings
E‐cigarettes delivered an average of 1.33 (0.87‐1.79) mg mean and 95% confidence interval (CI) of nicotine, and 93.8% of the inhaled dose, 1.22 (0.80‐1.66) was systemically retained. Average maximum plasma nicotine concentration (Cmax) was 8.4 (5.4–11.5) ng/ml and time of maximal concentration (Tmax) was 2–5 minutes. One participant had Tmax of 30 minutes. 84.4% and 91.7% of VG and PG, respectively, was systemically retained. Heart rate increased by an average of 8.0 beats per minute after 5 minutes. Withdrawal and urge to smoke decreased and the e‐cigarettes were described as satisfying.
Conclusions
E‐cigarettes can deliver levels of nicotine that are comparable to or higher than typical tobacco cigarettes, with similar systemic retention. Although the average maximum plasma nicotine concentration in experienced e‐cigarette users appears to be generally lower than what has been reported from tobacco cigarette use, the shape of the pharmacokinetic curve is similar, suggesting addictive potential.
: Electronic cigarettes (e-cigarettes) are a rapidly evolving class of tobacco products intended to deliver nicotine to users. There are many types of e-cigarettes available and the most popular type ...today in the United States are 'pod' based devices that use high nicotine concentration liquids. Understanding the nicotine delivery capabilities of e-cigarettes is imperative for understanding their addictive potential and safety profile, informing regulation, and revealing their potential use as smoking cessation aids.
: This review discusses nicotine content of e-cigarettes, effectiveness of nicotine aerosolization by devices, delivery of nicotine to users, and user and device characteristics that impact each of these.
: Modern e-cigarettes have the potential to deliver equal or more nicotine compared to a tobacco cigarette. Future research needs to identify the nicotine delivery profiles likely to benefit public health and the means to regulate them appropriately while also identifying those that are likely to cause harm. Public health benefit accrues if e-cigarettes help smokers quit combustible cigarettes completely. Harm is possible if inadequate nicotine delivery undermines cessation attempts, e-cigarettes facilitate continued combustible cigarette use, long-term e-cigarette use is associated with substantial morbidity/mortality, and/or e-cigarettes increase the initiation of combustible cigarette use among never smokers.
The article Nicotine inhibits activation of microglial proton currents via interactions with alpha7 acetylcholine receptors, written by Mami Noda and AI Kobayashi, was originally published Online ...First without open access. After publication in volume 67, issue 1, pages 235-245
In recent years, there has been rapid growth in the availability of innovative, non-combustible products, including oral tobacco-derived nicotine (OTDN) products, heated tobacco products (HTPs), and ...electronic cigarettes (also referred to as e-vapor products; EVPs). Industry, academic, and government researchers are developing and validating analytical methods to extract, separate, identify, and quantitate a variety of analytes from these innovative tobacco products using a wide range of analytical techniques. These analytes include constituents such as nicotine, degradants and impurities, flavors, non-tobacco ingredients, HPHCs, and other currently unknown constituents. In this Special Issue, we received nine contributions that covered the latest analytical methods that have been developed and applied for the chemical characterization or exposure assessment to tobacco product constituents of innovative non-combustible products. This Special Issue is representative of the importance of analytical sciences research in characterizing innovative non-combustible products for guiding product design, determining relative product performance, ensuring consistency during the manufacturing process, informing toxicological risk assessment, and enabling regulatory reporting. The current advances in the development and applications of the analytical methods reported in this Special Issue can be used to inform the harm reduction potential of innovative non-combustible products for adult smokers.
•Adolescents, young adults, and adults are increasingly using oral nicotine products including nicotine pouches, gum, lozenges, tablets, and toothpicks.•Nearly 1 in 3 participants had ever used an ...oral nicotine product (1 in 5 13–20-year-olds, 1 in 8 used in past 30 days, 1 in 10 in past 7 days).•Flavored nicotine pouches were the most used oral nicotine product in the past 30 days.•Favorable perceptions of product marketing is associated with an increased likelihood of buying oral nicotine products.
Oral nicotine products such as pouches, lozenges, tablets, gums, and toothpicks are gaining popularity, especially among adolescents and young adults, with increased marketing.
To estimate use patterns of oral nicotine products and likelihood of buying and liking products based on marketing, using a large group of adolescents, young adults, and adults.
A cross-sectional, online survey among U.S. participants (n = 6,131; ages 13–40 years) was conducted in November-December 2021.
Ever, past-30-day, and past-7-day use, behaviors, and flavors of oral nicotine products. Liking marketing and likelihood of buying specific oral nicotine products (Zyn pouches and Lucy gum) from marketing.
Our sample included 2,025 (33.0%) ever-users, 1,191 (19.4%) past-30-day users, and 998 (16.3%) past-7-day users of any oral nicotine product. Use patterns by age (in years): ever-users (<21: 816 (22.3%); 21–40: 1,209 (48.9%)); past-30-day users (<21: 458 (12.5%); 21–40: 733 (29.7%)); and past-7-day users (<21: 383 (10.5%); 21–40: 615 (24.9%)). Across products, 10–18% of participants reported using nicotine strength ranging from 6–10 mg. Fruit, sweet/dessert, alcohol, coffee, and mint were the most used flavors. When shown marketing, ever-users liked and were likely to buy Zyn pouches compared to never users, and participants under 21 years felt equally targeted by Lucy and Zyn marketing. Liking Zyn marketing even a little bit compared to not at all increased the likelihood of buying Zyn pouches across age groups. After observing marketing, participants < 21 years were more likely to buy Zyn if they perceived marketing to contain messages about good tasting flavors (AOR 1.43, 1.09–1.87; 0.009) and helping to feel comfortable in social situations (AOR 1.38, 1.02–1.87; 0.033), and were more likely to buy Lucy if they felt it could be used anywhere (AOR 1.57, 1.05–2.33; 0.026).
This study provides a foundation for estimating use, behaviors, flavors, and marketing influence of oral nicotine products in the US and globally. Adolescent and young adult use of oral nicotine products and likelihood of buying products when exposed to marketing highlights the need for expanded tobacco use surveillance, marketing regulations, and counter marketing and educational efforts.
E‐cigarettes, which deliver vaporized nicotine, have dramatically risen in popularity in recent years, despite many unanswered questions about safety, efficacy in reducing dependence, and overall ...impact on public health. Other factors, such as sex, also play an important role in determining behavioral and neurochemical responses to drugs of abuse. In these studies, we sought to develop a protocol for vaporized e‐cigarette nicotine self‐administration in rats, as a foundation to better understand the differing effects of nicotine exposure routes on behavior and physiological function. We report a novel method that elicits robust nicotine vapor self‐administration in male and female rats. Our findings indicate that 5‐mg/ml nicotine vape solution provides a high level of consistency in lever‐pressing behavior for both males and females. Moreover, in male rats, we find that such e‐cigarette nicotine vapor induces similar blood levels of nicotine's main metabolite, cotinine, as that found with intravenous nicotine self‐administration. Therefore, the breathing pattern during vapor exposure in males leads to similar levels of titrated nicotine intake as with intravenous nicotine self‐administration. Interestingly, a differential effect was found in the females, in which the same conditions of vapor exposure led to decreased cotinine levels with vapor compared to intravenous self‐administration. Finally, differences in nicotine‐mediated locomotion provide further support of the physiological effects of e‐cigarette vapor inhalation. Taken together, our findings reveal important sex differences in nicotine intake based on the route of exposure, and we further establish a protocol for nicotine vapor self‐administration in rats.
Given the recent increase in e‐cigarette/vape use worldwide, there has been a pressing need to better understand the impact of such vapor exposure on central and peripheral function. In these studies, we report a novel method that elicits robust nicotine vapor self‐administration in both males and females. By comparing the effects of vapor exposure to intravenous nicotine self‐administration, these studies also provide evidence of the differing effects of nicotine exposure routes and sex‐specific effects on physiological function.
PDF
