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An exponential rise in nicotine-containing electronic-cigarette use has been observed during the period of adolescence. Preclinical studies have shown that nicotine exposure during early adolescence, but not adulthood, increases subsequent drug intake and reward. Although growing clinical trends highlight that stimulant use disorders are associated with the opioid epidemic, very few studies have assessed the effects of adolescent nicotine exposure on opioid intake. The objective of our current study is to develop a new animal model to assess the causal relationship of adolescent nicotine exposure on subsequent opioid intake. In this effort, we first replicate previous studies using a well-established 4-day nicotine paradigm. Rats are pretreated with a low dose of nicotine (2 × , 30 μg/kg/0.1 mL, intravenous) or saline during early adolescence (postnatal days 28-31) or adulthood (postnatal days 86-89). Following nicotine pretreatment on postnatal day 32 or postnatal day 90, animals underwent operant intravenous self-administration for the psychostimulant, cocaine [500 μg/kg/infusion (inf)] or the opioid, fentanyl (2.5 μg/kg/inf). We successfully show that adolescent but not adult, nicotine exposure enhances cocaine self-administration in male rats. Furthermore, we illustrate early adolescent but not adult nicotine exposure enhances fentanyl self-administration, independent of sex. Overall, our findings highlight that adolescence is a unique period of development that is vulnerable to nicotine-induced enhancement for cocaine and fentanyl self-administration in rats.

Electronic cigarettes are the most common form of nicotine delivery used by youth and young adults, and in 2018, the US Surgeon General declared this to be an epidemic. The developing adolescent brain is vulnerable to nicotine exposure, which can lead to long-lasting cognitive and mood disorders. Screening rates for vaping are low and lack of knowledge by adolescents, clinicians, parents, and caregivers is high. This article reviews the components of vaping, prevalence, adverse reactions, regulation, treatment, and prevention strategies related to vaping in youth and young adults.

With the rise of e-cigarette use, teen nicotine exposure is becoming more widespread. Findings from clinical and preclinical studies show that the adolescent brain is particularly sensitive to nicotine. Animal studies have demonstrated that adolescent nicotine exposure increases reinforcement for cocaine and other drugs. However, the mechanisms that underlie these behaviors are poorly understood. Here, we report reactive microglia are critical regulators of nicotine-induced increases in adolescent cocaine self-administration. Nicotine has dichotomous, age-dependent effects on microglial morphology and immune transcript profiles. A multistep signaling mechanism involving D2 receptors and CX3CL1 mediates nicotine-induced increases in cocaine self-administration and microglial activation. Moreover, nicotine depletes presynaptic markers in a manner that is microglia-, D2- and CX3CL1-dependent. Taken together, we demonstrate that adolescent microglia are uniquely susceptible to perturbations by nicotine, necessary for nicotine-induced increases in cocaine-seeking, and that D2 receptors and CX3CL1 play a mechanistic role in these phenomena.

Background As of March 2019, JUUL electronic cigarettes are the most popular e-cigarette on the U.S. market, but little is known of nicotine exposure and dependence on JUUL and user experience. Methods JUUL users participated in a community-based study involving questionnaires, saliva collection and a qualitative interview. Results Fifteen participants were enrolled (80% male, 53% White) and had an average age of 29.8 (standard deviation = 10) years. Daily exposure to nicotine assessed via salivary cotinine was similar to those reported for other e-cigarette and tobacco cigarette users in general. The majority reported low to moderate nicotine dependence. Qualitative interview themes included: the importance of social networks in adoption and use of the product; device features such as small size and vapor cloud reinforced product use; the product provided satisfaction compared to a tobacco cigarette; and a perceived sense of addiction to the product. Conclusions JUUL e-cigarettes expose users to levels of nicotine similar to other e-cigarettes but may be more satisfying due to unique device features. JUUL may be quite acceptable to tobacco cigarette smokers who are seeking to quit. However, it holds addictive potential and can reinforce long-term nicotine use.

Background Smoking has been associated with postoperative complications and mortality in bariatric surgery. The evidence for smoking is based on self-report and medical charts, which can lead to misclassification and miscalculation of the associations. Determination of cotinine can objectively define nicotine exposure. We determined the accuracy of self-reported smoking compared to cotinine measurement in three phases of the bariatric surgery trajectory. Methods Patients in the phase of screening (screening), on the day of surgery (surgery), and more than 18 months after surgery (follow-up) were consecutively selected. Self-reported smoking was registered and serum cotinine was measured. We evaluated the accuracy of self-reported smoking compared to cotinine, and the level of agreement between self-report and cotinine for each phase. Results In total, 715 patients were included. In the screening, surgery, and follow-up group, 25.6%, 18.0%, and 15.5%, respectively, was smoking based on cotinine. The sensitivity of self-reported smoking was 72.5%, 31.0%, and 93.5% in the screening, surgery, and follow-up group, respectively (p 95% in all groups (p Conclusions Underreporting of smoking occurs before bariatric surgery, mainly on the day of surgery. Future studies on effects of smoking and smoking cessation in bariatric surgery should include methods taking into account the issue of underreporting.

Reward uncertainty is a common characteristic of gambling and may powerfully enhance attraction to gambling-related cues, thus promoting maladaptive gambling behaviors in susceptible individuals. The co-occurrence of gambling disorder with tobacco use disorder (60.4%) suggests a common mechanism for their pathology, and comorbid anxiety (41.3%) might further promote the maintenance of these behaviors. However, it is unknown how nicotine or anxiety might contribute to cue and reward attraction, or promote disordered gambling behavior. In the present study, we investigated the effects of nicotine (0.4 mg/kg, SC) on the desire for uncertain rewards and their cues in male and female Sprague-Dawley rats. During an autoshaping task, rats learned to associate a lever + tone cue with the delivery of sucrose pellet rewards under either certain or uncertain (probability and magnitude) reward conditions. Subsequently, we tested the ability of gambling-like cues to serve as a conditioned reinforcer, and to promote motivation for sucrose rewards during a progressive ratio task. Finally, anxiety behavior was measured to examine its interaction with nicotine and uncertainty. Here, we found that nicotine enhanced attraction to the magazine under certain but not uncertain reward conditions, and increased cue-triggered behaviors. Conversely, in the progressive ratio task, exposure to uncertain conditions and nicotine enhanced motivation for reward, compared with certain conditions. These results suggest that nicotine may interact with both certain and uncertain reward conditions to increase cue-triggered behavior and enhance motivation for rewards, providing possible insight into the comorbid relationship between pathological gambling and tobacco use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Introduction Behavioral discrimination of nicotine has only recently been assessed in humans, administered mostly by nasal spray before the newly available Spectrum research cigarettes differing in nicotine content. Here we wanted to explore applicability of these procedures to assess discrimination of nicotine administered by e-cigarettes. Methods In this feasibility study, 16 adult smokers were tested on ability to discriminate e-cigarettes with nicotine concentrations of 36, 24, and 12 mg/ml, one per session (in that order), from a placebo (0 mg/ml), each identified only by letter code. Reliable discrimination was defined by accurately identifying which was which (i.e. nicotine vs placebo) on >85% of trials (i.e. ≥7 of 8; p Results Discrimination from placebo was shown with 36 mg/ml and with 24 mg/ml nicotine in 15 of 16 subjects, but only 10 discriminated placebo from 12 mg/ml nicotine. Subjective items previously related to acute nicotine exposure (“how much nicotine”, “head rush/buzzed” on 0–100 VAS) generally showed nicotine concentration-dependent effects, as expected, but so did “throat irritation”. Conclusions Preliminary results confirm feasibility of using our behavioral procedure to assess ability to discriminate nicotine administered via these e-cigarettes, broadening generalizability of this procedure beyond nicotine via nasal spray and smoked tobacco cigarettes. Findings also suggest its applicability with testing discrimination of nicotine via other methods of rapid dosing (e.g., hookah, novel products), including the newer e-cigarette products. Further study with larger samples may identify individual difference and other factors influencing nicotine discrimination administered via e-cigarettes and other products.

Introduction During adolescence, exposure to nicotine or cannabis independently induces effects on neuromaturation and later cognitive function. However, the potential effect of both drugs under co-use conditions has become of increasing concern given the prevalence of e-cigarettes, legalization of cannabis, and availability of synthetic “spice” cannabinoid agonists. Aims and Methods The current studies investigated the effects of exposure to a cannabinoid receptor agonist (WIN55,212-2) and/or nicotine over a discrete time period in mid-adolescence on later intravenous nicotine self-administration in adult male and female mice. We further examined whether cannabinoid agonist administration in adulthood would alter nicotine reinforcement, with either acute or chronic pairing across 7 days. Results We found that adult males exhibited increased nicotine self-administration at a lower, rewarding nicotine dose following adolescent cannabinoid exposure, either alone or with nicotine coadministration. In contrast, adult females demonstrated an opposing effect in which adolescent cannabinoid and nicotine coexposure resulted in decreased nicotine intake compared with the nicotine only and control groups. Furthermore, after maintaining nicotine self-administration across sessions, pretreatment with a low dose of the cannabinoid agonist decreased nicotine intake in both male and female control mice, and this lowering effect was evidenced after both acute and chronic treatment. However, the cannabinoid agonist was ineffective in altering nicotine intake in mice previously exposed to nicotine, cannabinoid agonist, or both during adolescence. Conclusions These data provide evidence that adolescent drug exposure can alter later nicotine reinforcement in a sex-specific manner and can further modulate the effectiveness of interventions in reducing nicotine intake during adulthood. Implications These studies demonstrate a significant impact of nicotine, cannabinoids, or coexposure on developmental processes during adolescence. Differential effects were observed within each sex, with opposing results found for cannabinoid exposure on nicotine intake in males and females. Intriguingly, we also evidenced resistance to the lowering effects of a cannabinoid agonist on nicotine intake in adulthood based on adolescent drug exposure. Thus, these findings have important implications for our understanding of the impact of nicotine and cannabinoids (eg, Δ9-tetrahydrocannabinol (THC) and synthetic “spice” cannabinoids) during development, with further implications for the effectiveness of therapeutic interventions based on prior drug exposure in youth.

Adolescence is a time of major plasticity of brain systems that regulate motivated behavior and cognition, and is also the age of peak onset of nicotine use. Although there has been a decline in teen use of cigarettes in recent years, there has been a huge increase in nicotine vaping. It is therefore critically important to understand the impact of nicotine on this critical phase of brain development. Animal studies have shown that nicotine has unique effects on adolescent brain. The goal of this review is therefore to systematically evaluate age- and sex-differences in the effects of nicotine on brain and behavior. Both acute and chronic effects of nicotine on brain biochemistry and behavior, particularly drug reward, aversion, cognition and emotion, are evaluated. Gaps in our current knowledge that need to be addressed are also highlighted. This review compares and integrates human and animals findings. Although there can be no experimental studies in humans to confirm similar behavioral effects of teen nicotine exposure, an emerging observational literature suggests similarities across species. Given the substantial evidence for long-term negative impact of adolescent nicotine exposure on brain and behavior, further longitudinal assessment of health outcomes in teen and young adult e-cigarette users is warranted.

We used data from the 2016 and 2017 SummerStyles survey (N = 4,186 and 4,066, respectively) to assess US adults’ perceptions about the harms of nicotine in electronic vapor products (EVP) to the developing adolescent brain. Of respondents in 2016, 68.5% agreed exposure to nicotine in EVP was harmful, and of respondents in 2017, 62.6% agreed (P < .001). This agreement varied by several covariates. Continued efforts are warranted to educate the public about the risks of EVP use among youth, including the harmful effects of nicotine exposure on the developing adolescent brain.

Background Adolescent nicotine exposure increases methamphetamine (MA) intake in adult male rats; however, little is known about how nicotine affects MA self-administration during the adolescent period. Therefore, we assessed whether exposing rats to nicotine during early or late adolescence affects oral MA self-administration. Methods 146 male and female rats were treated with saline or nicotine (0.16 or 0.64 mg/kg) from postnatal day (PD) 25-PD 34 (the early exposure phase) and/or PD 35-PD 55 (the late exposure phase). Rats began an oral MA self-administration procedure on PD 35. Results Only the sex variable, but not nicotine, affected sucrose and MA acquisition, as female rats had more nose pokes than males during training. On the test sessions, female rats exposed to nicotine (0.64 mg/kg) in the early exposure phase had more active nose pokes than saline-treated female rats or nicotine-treated male rats. Rats exposed to nicotine (0.16 mg/kg) in the late exposure phase had fewer active nose pokes during testing than rats exposed to saline. Nose poke responding during extinction was not altered by nicotine exposure, but administering nicotine (0.16 or 0.64 mg/kg) to male rats in the early exposure phase did decrease nose pokes during the drug-primed reinstatement session. Conclusions Our results show that adolescent female rats are more sensitive to the reinforcing effects of oral sucrose and MA than adolescent males, and that preadolescent nicotine exposure enhances oral MA self-administration in female rats. These findings suggest that preteen nicotine use may increase vulnerability to later MA abuse in teenage girls.

Background: \ud Growth of e-cigarette use among smokers has raised concerns over uptake by non-smokers, particularly young people. Legislative changes aimed in part at reducing youth exposure to e-cigarettes include the EU Tobacco Products Directive (TPD). A core justification for such measures is the belief that e-cigarettes can lead to tobacco smoking through mechanisms of renormalisation including: mimicking and normalizing the act of smoking; increasing product acceptability via marketing; nicotine exposure. These mechanisms are here explored in relation to findings from qualitative research.\ud \ud Methods: \ud This paper reports results from twenty-one group interviews with 14–15 year olds in Wales, England and Scotland, conducted as part of an ongoing evaluation of the impact of the TPD on youth smoking and e-cigarette use. Interviews were conducted around the end of the transitional period for TPD implementation, and explored perceptions of e-cigarettes and tobacco, as well as similarities and differences between them.\ud \ud Results: \ud Young people differentiated between tobacco and e-cigarettes, rejecting the term e-cigarette in favour of alternatives such as ‘vapes’. Experimental or occasional use was common and generally approved of where occurring within social activity with peers. However, regular use outside of this context was widely disapproved of, unless for the purpose of stopping smoking. Increased prevalence of e-cigarettes did not challenge strongly negative views of smoking or reduce perceived harms caused by it, with disapproval of smoking remaining high. Nicotine use was variable, with flavour a stronger driver for choice of e-liquid, and interest more generally.\ud \ud Conclusion: \ud The extent to which participants differentiated between vaping and smoking, including styles and reasons for use in adults and young people; absence of marketing awareness; and continued strong disapproval of smoking provides limited support for some of the potential mechanisms through which e-cigarettes may renormalise smoking. However caution over nicotine exposure is still necessary.

Cigarette smoke is an aerosol containing microparticles that carry nicotine into the lung alveolar region where nicotine is rapidly absorbed into circulation. Nicotine exposure in smokers is a chronic intermittent process, with episodic intake during wakefulness and abstinence during sleep resulting in circadian fluctuation of blood nicotine levels. We developed an integrated platform where freely moving rodents can be exposed to episodic nicotine aerosol on an investigator-designed schedule. Plasma nicotine and its metabolite cotinine levels were determined with a LC-MS/MS method. We characterized the aerosol in the breathing zone of the rodent exposure chamber. The droplet-size distribution was within the respirable diameter range. The system can generate a wide range of nicotine concentrations in air that meet a variety of experimental needs. Rats were exposed to nicotine aerosol once every half hour in the dark phase of 12:12-h light-dark cycles for 10 days. We optimized the parameters of aerosol generation and exposure: plasma nicotine and cotinine concentrations reached 30–35 and 190–240 ng/ml, respectively. The nicotine levels and circadian patterns resembled the pharmacokinetic pattern of human smokers. In summary, we developed an aerosol system that can produce clinically relevant chronic intermittent nicotine exposure in unanesthetized, unrestrained rodents with route of administration and circadian blood pharmacokinetics resembling human smokers. This methodology is a novel tool for understanding the health effects of chronic intermittent nicotine exposure such as with tobacco cigarettes and electronic cigarettes for studies of behavior, pharmacology and toxicology, nicotine addiction, tobacco-related diseases, and teratogenicity, and for the discovery of therapeutics. NEW & NOTEWORTHY We developed a lung alveolar region-targeted aerosol method and a system that provides chronic intermittent nicotine exposure in freely moving rodents. The method produces in rodents clinically relevant nicotine exposure with the route and circadian pharmacokinetics resembling human smokers. This method is a novel tool for understanding the health impacts of chronic nicotine exposures such as with tobacco cigarettes and electronic cigarettes, for studying nicotine pharmacology, toxicology, addiction, and tobacco-related diseases, and for the discovery of therapeutics.

Waterpipe tobacco smoking (WTS) exposes users to toxicants in much greater amounts than a cigarette. Little is known about how gender affects WTS toxicant exposure and subjective response. Data from three clinical laboratory studies examining WTS conducted between 2008 and 2013 were combined for analysis. Participants (n=99; 38 women) completed a 45-minute WTS session where they smoked tobacco from a waterpipe ad libitum. Puff topography was measured throughout sessions, and plasma nicotine concentration, expired CO, and subjective responses were measured pre- and post-WTS. There was a gender effect for total puff volume with men inhaling a greater volume of smoke, on average (mean=59.9 L, SD=40.7), compared to women (mean=38.8 L, SD=27.8; p

We tested the hypothesis that nicotine exposure in utero and after birth [developmental nicotine exposure (DNE)] disrupts development of glycinergic synaptic transmission to hypoglossal motoneurons (XIIMNs). Glycinergic spontaneous and miniature inhibitory postsynaptic currents (sIPSC/mIPSC) were recorded from XIIMNs in brain stem slices from 1- to 5-day-old rat pups of either sex, under baseline conditions and following stimulation of nicotinic acetylcholine (ACh) receptors with nicotine (i.e., an acute nicotine challenge). Under baseline conditions, there were no significant effects of DNE on the amplitude or frequency of either sIPSCs or mIPSCs. In addition, DNE did not alter the magnitude of the whole cell current evoked by bath application of glycine, consistent with an absence of change in postsynaptic glycine-mediated conductance. An acute nicotine challenge (bath application of 0.5 μM nicotine) increased sIPSC frequency in the DNE cells, but not control cells. In contrast, nicotine challenge did not change mIPSC frequency in either control or DNE cells. In addition, there were no significant changes in the amplitude of either sIPSCs or mIPSCs in response to nicotine challenge. The increased frequency of sIPSCs in response to an acute nicotine challenge in DNE cells reflects an enhancement of action potential-mediated input from glycinergic interneurons to hypoglossal motoneurons. This could lead to more intense inhibition of hypoglossal motoneurons in response to exogenous nicotine or endogenous ACh. The former would occur with smoking or e-cigarette use while the latter occurs with changes in sleep state and with hypercapnia.NEW & NOTEWORTHY Here we show that perinatal nicotine exposure does not impact baseline glycinergic neurotransmission to hypoglossal motoneurons but enhances glycinergic inputs to hypoglossal motoneurons in response to activation of nicotinic acetylcholine (ACh) receptors with acute nicotine. Given that ACh is the endogenous ligand for nicotinic ACh receptors, the latter reveals a potential mechanism whereby perinatal nicotine exposure alters motor function under conditions where ACh release increases, such as the transition from non-rapid-eye movement to rapid-eye movement sleep, and during hypercapnia.

There is concern that youth e-cigarette use may serve as a gateway to cigarette smoking, and that nicotine exposure may harm brain development. It is therefore important to know how much nonsmoking youth perceive being exposed to nicotine through e-cigarettes.Data on smoking and vaping from the 2016 Monitoring the Future survey of eighth, tenth, and 12th grade students were analyzed in 2017. The weighted percentage distributions of self-reported e-cigarette mist last inhaled were calculated according to ever-smoking status and past 30-day smoking frequency. Chi-square tests of the association between smoking status and use of e-cigarettes perceived to contain nicotine, marijuana or hash oil, or just flavoring were performed. Never smokers and regular smokers were compared regarding the type of e-cigarette mist they believe they last used.A significant relationship exists between smoking behavior and reportedly vaping nicotine (p0.01) or just flavors (p0.01). With increasing smoking intensity, an increasing proportion of students report they are vaping nicotine; a decreasing proportion report just flavors. Among 12th graders, prevalence of vaping nicotine is lowest among never smokers and non-current smokers (14.3% and 18.1%) and highest among current and frequent smokers (61.3% and 60.9%, p0.01). Substantially larger proportions of never smokers and 30-day nonsmokers report vaping just flavors (76.0% and 69.6%) compared with regular or frequent smokers (31.0% and 29.3%, p0.01).Most nonsmoking students perceive limited nicotine exposure from vaping. Future research should evaluate the accuracy of self-reported e-cigarette nicotine content and monitor students who are consciously using nicotine-based e-cigarettes.

Our previous studies showed that paternal nicotine exposure can lead to hyperactivity in the offspring. Nevertheless, the cross-generational effects of maternal and biparental nicotine exposure remain unclear. In this study, female and male mice were exposed respectively by nicotine before pregnancy. The maternal pre-pregnancy nicotine exposure led to depression-like behaviors in the F1 offspring. However, after biparental pre-pregnancy nicotine exposure, seventy percentage of the offspring exhibited a depressive phenotype while 20% were hyperactive, and the remaining exhibited no obvious abnormal behavior. The cross-generational effects appeared to be mediated via disruption of the balance between GSK3 and p-GKS3 by nicotine. These results suggested that pre-pregnancy nicotine exposure can induce alterations in the behavior of the offspring, and the cross-generational effects of maternal nicotine exposure were particularly serious.

Conditioned stimuli contribute to the resilience of nicotine addiction in that nicotine-associated cues can influence smokers and promote relapse. These stimuli are thought to acquire incentive motivational properties through a Pavlovian mechanism, and this phenomenon can be measured in animals by observing conditioned approach to the conditioned stimulus (sign-tracking) or to the location of unconditioned stimulus delivery (goal-tracking). Goal-tracking is thought to be more flexible than sign-tracking in response to changes in expected outcome. Nicotine exposure can increase the expression of conditioned responses, and we hypothesized that animals exposed to nicotine would also exhibit less flexible conditioned responses after a change in the expected unconditioned stimulus. Adult male rats were exposed to nicotine (0.4mg/kg, s.c.) or saline before Pavlovian conditioned approach training sessions. After training, animals underwent test sessions that reduced (water substitution) or withheld (omission) the unconditioned stimulus (US, 20% sucrose). As expected, nicotine enhanced sign- and goal-tracking. Water substitution moderately and nonspecifically reduced both sign- and goal-tracking in all rats. In contrast, US omission only reduced goal-tracking, with robust effects in saline-exposed rats and smaller effects in nicotine-exposed rats. These data support the hypothesis that both sign-tracking and nicotine exposure confer behavioral inflexibility under US omission.

Introduction Reducing the level of nicotine in cigarettes is a regulatory strategy that has the potential to greatly improve public health. If nicotine levels are reduced in all commercially available cigarettes, current smokers might find it easier to quit and young people might be less likely to become dependent. However, it is not yet known whether age moderates subjective or behavioral responses to low-nicotine cigarettes. Methods Recently, a large, multisite randomized clinical trial was conducted to compare the effects of cigarettes differing in nicotine content (either usual-brand or research cigarettes containing 15.8, 5.2, 2.4, 1.3, or 0.4 mg nicotine/g tobacco) across 6 weeks of exposure. In this secondary analysis, we tested whether age moderated smokers' subjective (measures of psychological reward, smoking satisfaction) and behavioral (cigarettes smoked per day, smoking topography, and nicotine exposure) responses to cigarettes varying in nicotine content after 2 and 6 weeks of use, while controlling for baseline dependence and demographic factors. Results Results indicated that younger adults (age 18-24) who smoked cigarettes with 2.4-0.4 mg/g nicotine reported significantly less smoking satisfaction and psychological reward, and smoked fewer cigarettes per day, than older adults (25+ years) after 2 weeks of use. No differences in topography were observed at either time point. After 6 weeks of use, differences had diminished on all measures. Conclusions The reduced positive effects of reduced-nicotine content cigarettes in young adults suggests that this regulatory policy may reduce smoking reinforcement in this vulnerable population. Implications As the FDA considers reducing the level of nicotine in cigarettes to make them less addictive, understanding the potential impact of this policy on young people is of crucial importance. We found that young adults had significantly lower positive subjective effects to very-low nicotine content (VLNC) cigarettes and smoked fewer VLNC cigarettes than older adults after 2 weeks of use, indicating that this policy may reduce smoking reinforcement more quickly in young adults. These data add to the growing body of evidence on the potential for this policy to positively affect public health.

BACKGROUND AND OBJECTIVES: Secondhand smoke (SHS) directly increases exposure to airborne nicotine, tobacco’s main psychoactive substance. When exposed to SHS, nonsmokers inhale 60% to 80% of airborne nicotine, absorb concentrations similar to those absorbed by smokers, and display high levels of nicotine biomarkers. Social modeling, or observing other smokers, is a well-established predictor of smoking during adolescence. Observing smokers also leads to increased pharmacological exposure to airborne nicotine via SHS. The objective of this study is to investigate whether greater exposure to airborne nicotine via SHS increases the risk for smoking initiation precursors among never-smoking adolescents. METHODS: Secondary students (N = 406; never-smokers: n = 338, 53% girls, mean age = 12.9, SD = 0.4) participated in the AdoQuest II longitudinal cohort. They answered questionnaires about social exposure to smoking (parents, siblings, peers) and known smoking precursors (eg, expected benefits and/or costs, SHS aversion, smoking susceptibility, and nicotine dependence symptoms). Saliva and hair samples were collected to derive biomarkers of cotinine and nicotine. Adolescents wore a passive monitor for 1 week to measure airborne nicotine. RESULTS: Higher airborne nicotine was significantly associated with greater expected benefits (R2 = 0.024) and lower expected costs (R2 = 0.014). Higher social exposure was significantly associated with more temptation to try smoking (R2 = 0.025), lower aversion to SHS (R2 = 0.038), and greater smoking susceptibility (R2 = 0.071). Greater social exposure was significantly associated with more nicotine dependence symptoms; this relation worsened with higher nicotine exposure (cotinine R2 = 0.096; airborne nicotine R2 = 0.088). CONCLUSIONS: Airborne nicotine exposure via SHS is a plausible risk factor for smoking initiation during adolescence. Public health implications include limiting airborne nicotine through smoking bans in homes and cars, in addition to stringent restrictions for e-cigarettes.

The first symptoms of schizophrenia (SCHZ) are usually observed during adolescence, a developmental period during which first exposure to psychoactive drugs also occurs. These epidemiological findings point to adolescence as critical for nicotine addiction and SCHZ comorbidity, however it is not clear whether exposure to nicotine during this period has a detrimental impact on the development of SCHZ symptoms since there is a lack of studies that investigate the interactions between these conditions during this period of development. To elucidate the impact of a short course of nicotine exposure across the spectrum of SCHZ-like symptoms, we used a phencyclidine-induced adolescent mice model of SCHZ (2.5mg/Kg, s.c., daily, postnatal day (PN) 38-PN52; 10mg/Kg on PN53), combined with an established model of nicotine minipump infusions (24mg/Kg/day, PN37-44). Behavioral assessment began 4 days after the end of nicotine exposure (PN48) using the following tests: open field to assess the hyperlocomotion phenotype; novel object recognition, a declarative memory task; three-chamber sociability, to verify social interaction and prepulse inhibition, a measure of sensorimotor gating. Phencyclidine exposure evoked deficits in all analyzed behaviors. Nicotine history reduced the magnitude of phencyclidine-evoked hyperlocomotion and impeded the development of locomotor sensitization. It also mitigated the deficient sociability elicited by phencyclidine. In contrast, memory and sensorimotor gating deficits evoked by phencyclidine were neither improved nor worsened by nicotine history. In conclusion, our results show for the first time that nicotine history, restricted to a short period during adolescence, does not worsen SCHZ-like symptoms evoked by a phencyclidine-induced mice model.

Adolescent nicotine exposure has been shown to lead to further psychostimulant use in adulthood. Previous preclinical research in rats has shown that environmental enrichment may protect against drug abuse vulnerability. The current study was designed to examine whether environmental enrichment can block the ability of adolescent nicotine exposure to increase d-amphetamine self-administration in adulthood. Male Sprague-Dawley rats were raised in either enriched conditions (ECs) or isolated conditions (ICs) and then injected with saline or nicotine (0.4 mg/kg, sc) for 7 days during adolescence. In adulthood rats were allowed to self-administer d-amphetamine under a fixed ratio (FR; 0, 0.006, 0.01, 0.02, 0.06, and 0.1 mg/kg/infusion) and progressive ratio (PR; 0, 0.006, 0.06, and 0.1 mg/kg/infusion) schedule of reinforcement. Nicotine-treated IC rats self-administered more d-amphetamine at 0.006, 0.01, and 0.02 mg/kg/infusion doses compared with their saline-treated IC counterparts regardless of the schedule maintaining behavior. This effect of nicotine was reversed in EC rats on a fixed ratio schedule. These findings indicate that environmental enrichment can limit the ability of adolescent nicotine exposure to increase vulnerability to other psychostimulant drugs, such as d-amphetamine. (PsycINFO Database Record

The long-term consequences of early life nicotine exposure are poorly defined. Approximately 8–10% of women report smoking during pregnancy, and this may promote aberrant development in the offspring. To this end, we investigated potential enduring effects of perinatal nicotine exposure on murine sleep and affective behaviors in adulthood (~13–15 wk of age) in C57Bl6j mice. Mothers received a water bottle containing 200 µg/ml nicotine bitartrate dihydrate in 2% wt/vol saccharin or pH-matched 2% saccharin with 0.2% (vol/vol) tartaric acid throughout pregnancy and before weaning. Upon reaching adulthood, offspring were tested in the open field and elevated plus maze, as well as the forced swim and sucrose anhedonia tests. Nicotine-exposed male (but not female) mice had reduced mobility in the open field, but no differences were observed in anxiety-like or depressive-like responses. Upon observing this male-specific phenotype, we further assessed sleep-wake states via wireless EEG/EMG telemetry. Following baseline recording, we assessed whether mice exposed to nicotine altered their homeostatic response to 5 h of total sleep deprivation and whether nicotine influenced responses to a powerful somnogen [i.e., lipopolysaccharides (LPS)]. Males exposed to perinatal nicotine decreased the percent time spent awake and increased time in non-rapid eye movement (NREM) sleep, without changes to REM sleep. Nicotine-exposed males also displayed exaggerated responses (increased time asleep and NREM spectral power) to sleep deprivation. Nicotine-exposed animals additionally had blunted EEG slow-wave responses to LPS administration. Together, our data suggest that perinatal nicotine exposure has long-lasting effects on normal sleep and homeostatic sleep processes into adulthood.

The emergence of new tobacco heating products and electronic nicotine delivery systems (ENDS) is changing the way humans are exposed to nicotine. The purpose of this narrative review is to provide a broad overview of published scientific literature with respect to the effects of nicotine on three key health-related areas: 1) cardiovascular risk, 2) carcinogenesis and 3) reproductive outcomes. These areas are known to be particularly vulnerable to the effects of cigarette smoke, and in addition, nicotine has been hypothesized to play a role in disease pathogenesis. Acute toxicity will also be discussed. The literature to February 2019 suggests that there is no increased cardiovascular risk of nicotine exposure in consumers who have no underlying cardiovascular pathology. There is scientific consensus that nicotine is not a direct or complete carcinogen, however, it remains to be established whether it plays some role in human cancer propagation and metastasis. These cancer progression pathways have been proposed in models in vitro and in transgenic rodent lines in vivo but have not been demonstrated in cases of human cancer. Further studies are needed to determine whether nicotine is linked to decreased fertility in humans. The results from animal studies indicate that nicotine has the potential to act across many mechanisms during fetal development. More studies are needed to address questions regarding nicotine exposure in humans, and this may lead to additional guidance concerning new ENDS entering the market.

OBJECTIVES: An association between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD) has been shown across several studies based on self-reports. No previous studies have investigated the association of nicotine exposure measured by cotinine levels during pregnancy and offspring ADHD. METHODS: In this population-based study, 1079 patients born between 1998 and 1999 and diagnosed with ADHD according to the International Classification of Diseases and 1079 matched controls were identified from Finnish nationwide registers. Maternal cotinine levels were measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank. RESULTS: There was a significant association between increasing log-transformed maternal cotinine levels and offspring ADHD. The odds ratio was 1.09 (95% confidence interval [CI] 1.06–1.12) when adjusting for maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child’s birth weight for gestational age. In the categorical analyses with cotinine levels in 3 groups, heavy nicotine exposure (cotinine level >50 ng/mL) was associated with offspring ADHD, with an odds ratio of 2.21 (95% CI 1.63–2.99) in the adjusted analyses. Analyses by deciles of cotinine levels revealed that the adjusted odds for offspring ADHD in the highest decile was 3.34 (95% CI 2.02–5.52). CONCLUSIONS: The study reveals an association with and a dose-response relationship between nicotine exposure during pregnancy and offspring ADHD. Future studies incorporating maternal smoking and environmental, genetic, and epigenetic factors are warranted.

Studies of intergenerational effects of parental chemical exposure have principally focused on maternal exposure, particularly for studies of adverse neurobehavioral consequences on the offspring. Maternal nicotine exposure has long been known to cause adverse neurobehavioral effects on the offspring. However, paternal toxicant exposure has also been found to cause neurobehavioral toxicity in their offspring. Recent work suggests that paternal nicotine exposure can have epigenetic effects, although it remains unclear whether such changes lead to neurobehavioral effects. In the current study, we investigated the effects of paternal nicotine exposure on neurobehavioral development of their offspring. Male Sprague-Dawley rats were exposed to 0 or 2 mg/kg/day nicotine (sc) for 56 consecutive days with two consecutive 2ML4 osmotic minipumps. Following treatment, these males were mated with drug-naive female rats. Offspring of both sexes were tested in a behavioral battery to assess locomotion, emotional function and cognition. Paternal nicotine exposure did not impact offspring viability, health or growth. However, behavioral function of the offspring was significantly altered by paternal nicotine exposure. Male offspring with paternal nicotine exposure exhibited locomotor hyperactivity in the Figure-8 apparatus when tested during adolescence. When retested in adulthood and regardless of sex, offspring of the nicotine exposed father showed significantly reduced habituation of locomotor activity over the course of the session. Compared to controls, female offspring of nicotine-exposed fathers showed significantly reduced response latency in the radial arm maze test. In addition to locomotor hyperactivity, the offspring of nicotine-exposed fathers also showed significantly diminished habituation in the novel object recognition test. These results indicate that chronic paternal nicotine exposure can impact the behavior of offspring, producing locomotor hyperactivity and impaired habituation.

Author(s): St Helen, Gideon; Nardone, Natalie; Addo, Newton; Dempsey, Delia; Havel, Christopher; Jacob, Peyton; Benowitz, Neal L | Abstract: AimTo describe systemic nicotine exposure and subjective effects of electronic cigarettes (e-cigarettes) in people who use both e-cigarettes and cigarettes (dual users), including within-subject comparisons of e-cigarette and cigarette use.DesignTwo-arm, counterbalanced cross-over study. Participants used their usual brand of e-cigarette or cigarette during a standardized session in a 2-week study.SettingHospital research ward, San Francisco, CA, USA.ParticipantsThirty-six healthy (eight women, 28 men) participants.MeasurementsPlasma nicotine was analyzed by gas chromatography-tandem mass spectrometry; nicotine withdrawal, urge to smoke and vape, affective states, craving, satisfaction and psychological reward were measured by standardized questionnaires.FindingsCompared with cigarettes, average maximum plasma nicotine concentration (Cmax ) was lower with e-cigarettes [6.1 ± 5.5 ng/ml, mean ± standard deviation (SD) versus 20.2 ± 11.1 ng/ml, P l 0.001] and time of maximal concentration (Tmax ) was longer (6.5 ± 5.4 versus 2.7 ± 2.4 minutes, P l 0.001). Use of both products resulted in a reduction in the severity of withdrawal symptoms, negative affect and urge to use either product. E-cigarettes were less rewarding and satisfying and reduced craving to a lesser degree than cigarettes. We were not able to detect any differences in withdrawal symptoms, affective states and urge to smoke cigarettes between e-cigarette and cigarette use.ConclusionSystemic nicotine exposure was, on average, lower with single use of e-cigarettes compared with cigarettes, and e-cigarettes were judged to be less satisfying and rewarding and reduced craving less than cigarettes.

Objective E-cigarettes are the most prevalent tobacco product used by adolescents. We sought to determine whether the presence of flavoring and/or the presence of nicotine at the first e-cigarette exposure predicted progression to current e-cigarette use (use in past 30 days) as well as escalation in use (number of days in the past 30 days) among adolescents. Methods Adolescents from public high schools outside of Philadelphia, PA completed in-classroom surveys at baseline (9th grade) and at 6-month intervals for the following 18 months (fall 2018, beginning of 11th grade). Adolescents who reported ever having used e-cigarettes at baseline (N = 354) comprised the analytical sample. Results We employed a two-part Latent Growth Curve Model including flavor, nicotine, and other covariates. Initial use of a flavored (vs unflavored) e-cigarette was associated with progression to current e-cigarette use (β = 0.54, z = 2.09, p = 0.04) and escalation in the number of days of e-cigarette use (β = 0.35, z = 2.58, p = 0.01) across the following 18 months. Initial use of an e-cigarette with nicotine (vs without nicotine) was associated with a greater number of days of e-cigarette use at baseline (β = 0.49, z = 2.16, p = 0.03). Conclusions The findings underscore the risk that flavoring and nicotine pose for progression beyond initial e-cigarette use. Regulations addressing flavoring and nicotine in e-cigarettes have the potential to reduce the number of adolescents who become current as well as frequent e-cigarette users.

Anxiety-related disorders are severe psychiatric conditions that involve complex physiological and behavioral maladaptive responses. The use of conspecific alarm substance (CAS) for inducing anxiety-like behaviors in fish species provides important translational insights of how aversive conditions modulate neurobehavioral functions. Because nicotine may elicit anxiolytic-like responses, here we investigated whether acute nicotine exposure prevents CAS-induced anxiogenic-like behaviors in zebrafish. We used both novel tank and light-dark tests as two well-established paradigms for measuring anxiety-like phenotypes. Fish were individually exposed to 1 mg/L nicotine or non-chlorinated water for 3 min and then transferred to other tanks in the absence or presence of 3.5 mL/L CAS for 5 min. Later, the behavior of fish was tested in the novel tank test or in the light-dark preference test. As expected, CAS triggered aversive behaviors by increasing bottom-dwelling, freezing, erratic movements, scototaxis, and risk assessment episodes. Nicotine alone elicited anxiolytic-like behaviors since it increased the time spent in the top, as well as the average duration of entry in the lit compartment. Moreover, nicotine pretreatment prevented CAS-induced aversive responses without changing locomotion, suggesting that anxiolysis could play a role, at least in part, to the behavioral effects of nicotine observed here. Overall, these novel findings show the beneficial effects of nicotine on anxiogenic responses in zebrafish. We also reinforce the practical advantages of this aquatic species to explore the relieving properties of nicotine, as well as to understand the neurobiological bases involved in anxiety-related disorders and associated therapeutic targets.

Summary Electronic nicotine delivery systems, or ENDS, are devices that heat and aerosolise a solution of propylene glycol, glycerine, nicotine, and flavourings. They have only achieved widespread use in the past 5 years or so, and therefore evidence around their potential to effect health is scarce. Importantly, they are often viewed as safer than tobacco cigarettes, meaning that at-risk populations, including pregnant women, might be more inclined to use them. No human studies, however, have assessed the potential for maternal ENDS use to effect the health of a developing baby. Experimental research suggests that nicotine alone is likely to adversely affect the fetus. Further, there is a misconception that ENDS do not produce second-hand aerosols. This misconception might put infants and young children at risk because their parents are more likely to use ENDS around them than they are to use tobacco cigarettes. Emerging evidence also proposes that nicotine and other substances produced by ENDS can deposit onto surfaces, and subsequently be exposed to infants and children; a process known as third-hand exposure. Finally, ENDS are often refillable, and instances of accidental poisonings of children who drink nicotine-containing refills have occurred. Thus, there are a multitude of ways that, with respect to early-life exposures and health, ENDS are a cause for concern.

Purpose This study examined changes in e-cigarette and dual-use frequency, levels of nicotine exposure and e-cigarette dependence, and device and e-liquid preferences over 12 months. Methods Adolescents (N = 173, aged 13–18 years) who reported past-month e-cigarette use and at least 10 lifetime uses were recruited from the San Francisco Bay Area. The sample was 75.1% male, 54.9% non-Hispanic White, mean age 16.6 years (standard deviation = 1.2); 26.6% reported past-month cigarette smoking at baseline (i.e., dual use). At baseline, 6-month, and 12-month follow-up, participants provided saliva samples for cotinine testing and self-reported e-cigarette use frequency, dependence, past-month smoking, product preference, and flavor preference. Results Most (80.3%) were still using e-cigarettes at 12 months, and daily use increased from 14.5% to 29.8%. Model testing indicated an overall increase from baseline to 12 months in frequency of e-cigarette use (F(2, 166) = 5.69, p = .004), dependence (F(2, 164) = 5.49, p = .005), and cotinine levels (F(2, 103) = 4.40, p = .038). Among those reporting only e-cigarette use at baseline, 28.8% reported combustible cigarette use during follow-up. Among those reporting dual use at baseline, 57.1% were still dual using at 12 months, 31.4% reported e-cigarette use only, and none abstained from both products. Higher nicotine delivering e-cigarette devices (i.e., Juul, mods) became more popular over time, whereas flavor preferences (i.e., fruit, mint/menthol, and candy) remained stable. Conclusions Adolescents' e-cigarette use persisted over a 12-month period with significant increases in frequency of use, nicotine exposure, and e-cigarette dependence. Transitions from single to dual and dual to single nicotine product use were observed in approximately one in three users over the study period.

Background The abuse liability of the JUUL System (JS) in four flavors were evaluated compared to combustible cigarettes, nicotine gum, and a comparator electronic nicotine delivery system (ENDS) with pharmacokinetics (PK) and subjective effects. Methods Adult smokers (N = 66; 50.0 % female; mean age = 41.1; 63.6 % white) completed a 7-arm within-subjects cross-over product-use study while confined to a clinical laboratory. Participants used JS in four flavors (Virginia Tobacco, Mango, Mint, Creme, [5.0 % nicotine; 59 mg/mL]), their usual brand (UB) cigarette, a comparator ENDS (VUSE Solo; 4.8 % nicotine, tobacco-flavor), and mint nicotine gum (4 mg) under controlled use conditions. After each product use, nicotine PK and subjective effects were assessed. Results Maximum plasma nicotine levels (Cmax-BL), rate of plasma nicotine rise, overall nicotine exposure (AUC0−60-BL), and subjective liking and satisfaction of JS were significantly lower than UB cigarettes. These parameters were generally greater for JS than nicotine gum; the comparator ENDS was somewhat lower but within the range of JS. Nicotine PK did not differ among the Mint, Mango, and Virginia Tobacco JS flavors. Mint and Mango were rated as more satisfying than Virginia Tobacco and Creme. Conclusions Controlled use of JS among adult smokers resulted in nicotine delivery, product liking, and satisfaction that were less than that of combustible cigarettes but generally greater than nicotine gum. These results support the conclusion that JS has lower abuse liability than combustible cigarettes, higher abuse liability than nicotine gum, and may provide sufficient nicotine delivery and satisfying effects to support substitution for combustible cigarettes among adult smokers.

Background To assess the abuse liability of the JUUL System (JS) in 5.0 % (59 mg/mL) and 3.0 % (35 mg/mL) nicotine concentrations. Methods Adult smokers (N = 146; 45.9 % female; mean age = 41.29 years) were randomized to one of four study flavor arms and then to a within-subjects cross-over sequence for five test product categories: (1) JS 5.0 % nicotine concentration; (2) JS 3.0 % nicotine; (3) usual brand (UB) cigarette; (4) 4 mg mint nicotine gum; (5) comparator ENDS (VUSE Alto 5.0 % nicotine). Products were tested by ad libitum use (5 min for ENDS and cigarette; 30 min for gum); nicotine pharmacokinetic (PK) parameters and subjective effects were assessed following use. Results Maximum plasma nicotine concentration (Cmax-BL), rate of plasma nicotine rise and total nicotine exposure (AUC0–60-BL) of UB cigarette were significantly greater than all other test products. The comparator ENDS was significantly greater than 5.0 % and 3.0 % JS and nicotine gum on Cmax-BL, rate of plasma nicotine rise, and AUC0–60-BL; Cmax-BL of JS 5.0 % was significantly greater than JS 3.0 % and nicotine gum. Product liking and satisfying effects were significantly highest for the UB cigarette; JS products and comparator ENDS did not significantly differ and were rated higher than nicotine gum on most subjective measures. Conclusions These results suggest that the abuse liability of both 5.0 % and 3.0 % JS is: (1) substantially lower than UB cigarette; (2) somewhat lower than comparator ENDS; and (3) higher than nicotine gum. Additionally, the abuse liability of JS 5.0 % is somewhat higher than JS 3.0 %.

Background The Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but may have unintended consequences related to weight gain. Methods Weight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.4 to 15.8 mg/g or their own usual brand for 6 weeks. Additional analyses evaluated weight gain in the lowest nicotine content cigarette groups (0.4 and 0.4 mg/g, high tar) to examine the effect of study product in compliant participants as assessed by urinary biomarkers. Differences in outcomes due to gender were also explored. Findings There were no significant differences in weight gain when comparing the reduced nicotine conditions with the 15.8 mg/g control group across all treatment groups and weeks. However, weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions. Within the 2 lowest nicotine content cigarette conditions, male and female smokers biochemically verified to be compliant on study product gained significantly more weight than non-compliant smokers and control groups. Conclusions The effect of random assignment to investigational cigarettes with reduced nicotine on weight gain was likely obscured by non-compliance with study product. Men and women who were compliant in the lowest nicotine content cigarette conditions gained 1.2 kg over 6 weeks, indicating weight gain is a likely consequence of reduced exposure to nicotine. Trial registration number NCT01681875, Post-results.

The Tobacco Heating System (THS) 2.2, a candidate Modified Risk Tobacco Product (MRTP), is designed to heat tobacco without burning it. Tobacco is heated in order to reduce the formation of harmful and potentially harmful constituents (HPHC), and reduce the consequent exposure, compared with combustible cigarettes (CC). In this 5-day exposure, controlled, parallel-group, open-label clinical study, 160 smoking, healthy subjects were randomized to three groups and asked to: (1) switch from CCs to THS 2.2 (THS group; 80 participants); (2) continue to use their own non-menthol CC brand (CC group; 41 participants); or (3) to refrain from smoking (smoking abstinence (SA) group; 39 participants). Biomarkers of exposure, except those associated with nicotine exposure, were significantly reduced in the THS group compared with the CC group, and approached the levels observed in the SA group. Increased product consumption and total puff volume were reported in the THS group. However, exposure to nicotine was similar to CC at the end of the confinement period. Reduction in urge-to-smoke was comparable between the THS and CC groups and THS 2.2 product was well tolerated.

Among numerous studies, perinatal nicotine exposure (PN) has had variable effects on respiratory control in the neonatal period. The effects of acute nicotine exposure on breathing are largely mediated by α4-containing nicotine acetylcholine receptors (nAChRs). These receptors are also involved in thermoregulatory responses induced by both acetylcholine and nicotine. We therefore hypothesized that α4-containing nAChRs would mediate the effects of PN on the metabolic and ventilatory responses of neonates to modest cold exposure. Wild-type (WT) and α4 knockout (KO) mice were exposed to 6 mg·kg−1·day−1 nicotine or vehicle from embryonic day 14. At postnatal day (P) 7 mice were cooled from an ambient temperature (TA) of 32 to 20°C. Body temperature (TB), rate of O2 consumption (V̇o2), ventilation (V̇e), respiratory frequency (FB), and tidal volume (VT) were continually monitored. An absence of α4 had no effect on the metabolic response to ambient cooling. Surprisingly, PN selectively increased the metabolic response of KO pups to cooling. Regardless, KO pups became hypothermic to the same degree as WT pups, and for both genotypes the drop in TB was exacerbated by PN. PN led to hyperventilation in WT pups caused by an increase in VT, an effect that was absent in α4 KO littermates. We show that PN interacts with α4-containing nAChRs in unique ways to modulate the control of breathing and thermoregulation in the early postnatal period.

Adolescence represents a unique developmental period associated with increased risk-taking behavior and experimentation with drugs of abuse, in particular nicotine. We hypothesized that exposure to nicotine during early adolescence might increase the risk for drug reward in adulthood. To test this hypothesis, male ICR mice were treated with a subchronic regimen of nicotine or saline during adolescence, and their preference for cocaine, morphine and amphetamine was examined using the conditioned place preference (CPP) test in adulthood. Long-term behavioral changes induced by nicotine suggested a possible role of altered gene transcription. Thus, immunoblot for ΔFosB, a member of the Fos family of transcription factors, was conducted in the nucleus accumbens of these mice. Mice treated with nicotine during early but not late adolescence showed an increase in CPP for cocaine, morphine and amphetamine later in adulthood. This effect was not seen in mice pretreated with a subchronic regimen of nicotine as adults, suggesting that exposure to nicotine specifically during early adolescence increases the rewarding effects of other drugs in adulthood. However, adolescent nicotine exposure did not alter highly palatable food conditioning in mice. The enhancement of cocaine CPP by nicotine was strain-dependent and was blocked by pretreatment with nicotinic antagonists. In addition, nicotine exposure during early adolescence induced ΔFosB expression to a greater extent than identical nicotine exposure in adulthood, and enhanced cocaine-induced locomotor sensitization later in adulthood. These results suggest that nicotine exposure during early adolescence increases drug-induced reward in adulthood through mechanisms that may involve the induction of ΔFosB.

Background: African American (AA) smokers experience greater tobacco-related disease burden than Whites, despite smoking fewer cigarettes per day (CPD). Understanding factors that influence daily nicotine intake in AA smokers is an important step toward decreasing tobacco-related health disparities. One factor of interest is smoking topography, or the study of puffing behavior. Aims: (i) to create a model using puff characteristics, nicotine dependence, and nicotine metabolism to predict daily nicotine exposure, and (ii) to compare puff characteristics and nicotine intake from two cigarettes smoked at different times to ensure the reliability of the puff characteristics included in our model. Methods: Sixty AA smokers smoked their preferred brand of cigarette at two time points through a topography device. Plasma nicotine, expired CO, and changes in subjective measures were measured before and after each cigarette. Total nicotine equivalents (TNE) was measured from 24-hour urine collected during ad libitum smoking. Results: In a model predicting daily nicotine exposure, total puff volume, CPD, sex, and menthol status were significant predictors (R2 = 0.44, P < 0.001). Total puff volume was significantly greater and inter-puff intervals were significantly shorter after ad lib smoking compared with the first cigarette of the day, but puffing behaviors for both cigarettes were highly correlated (r range = 0.69–0.89, P < 0.001) within-subjects. Conclusion: This is the first study, to our knowledge, to show that puff characteristics of individual cigarettes are predictive of daily nicotine intake. Impact: These findings enhance our understanding of the relationship between smoking behavior and nicotine intake in AA smokers. Cancer Epidemiol Biomarkers Prev; 25(6); 936–43. ©2016 AACR.

Introduction While cigarette smoking rates have been steadily decreasing over the past decade, there has been a dramatic increase in nicotine use via e-cigarettes, especially during adolescence. Adolescent e-cigarette use is associated with a greater risk of future cigarette smoking, and increased rates of cigarette smoking in individuals who may have otherwise never tried cigarettes. In humans and rodents, early initiation of nicotine use has been associated with greater consumption, dependence, and persistent nicotine use. The present study sought to investigate the long-lasting effect of daily high-dose nicotine exposure during adolescence on nicotine consumption in adulthood. Method Male Sprague-Dawley rats were exposed daily to nicotine (1.0 mg/kg, subcutaneous), or vehicle (1 mL/kg saline, subcutaneous) during adolescence (post-natal day [P] 28–41). Adult nicotine self-administration (0.02 mg/kg/infusion, intravenous) was assessed beginning on P75 on fixed-ratio 1 (FR1), fixed-interval 1 min (FI1), and progressive ratio (PR) schedules of reinforcement. Results Adolescent nicotine pre-exposure did not affect adult nicotine self-administration on the simple FR1 schedule, however increased intake and responding for nicotine was observed when a short delay was implemented on an FI1 schedule of reinforcement. Conclusions Adolescence is a critical period when the brain is especially vulnerable to the effects of nicotine. Nicotine exposure in adolescence enhances susceptibility to increased nicotine intake in adulthood on a reinforcement schedule more reflective of human nicotine intake patterns, and this effect can extend into adulthood even after termination of nicotine exposure during adolescence.

BACKGROUND. Although weight-related reasons for smoking and vaping have been examined in adults, research in adolescents is lacking. Thus, we examined the prevalence and correlates of using flavored e-liquids for appetite control or weight loss in high school adolescents. METHODS. The analytic sample included 529 students who completed a school-based survey in Connecticut in Spring 2017 (50.6% female, 79.5% White, mean age 16.27 [SD=1.18], range 13–19 years). Inclusion criteria were past-30-day vaping, using ≥1 flavored e-liquid (past month), and having non-missing data on flavored e-liquid use for appetite control and weight loss. Participants reported on sex, age, race, past-30-day vaping and smoking frequency, nicotine e-liquid use, flavored e-liquid use (e.g., tobacco, mint, fruit, candy), and flavored e-liquid use for appetite control and/or weight loss. RESULTS. Adolescent e-cigarette users (past 30-days) reported vaping flavored e-liquids for appetite control (13.8%) and weight loss (9.3%). Using flavored e-liquids for appetite control or weight loss, respectively, was associated with more frequent vaping (OR = 1.21; 1.21) and using more flavored e-liquids (OR = 1.33; 1.28, p-values < .01). Vaping candy-flavored e-liquids (OR = 1.16, p = 0.02) uniquely was associated with vaping for appetite control. CONCLUSIONS. A subset of adolescents reported using flavored e-liquids for weight-related reasons. These adolescents reported vaping more frequently than their counterparts, raising concerns about increased nicotine exposure. Research is needed to understand where adolescents learn about weight-motivated vaping (e.g., friends, social media) and whether weight-related motives promote e-cigarette initiation among e-cigarette naïve individuals or continued/escalating use among current users.

Chronic administration of nicotine or exposure to stress can produce long-lasting behavioral and physiological changes in humans and animals alike. Further, the impact of nicotine and stress exposure can be inherited by offspring to produce persistent changes in physiology and behavior. To determine if nicotine and stress interact across generations to influence offspring behavior we exposed F0 male mice to nicotine and F1 male and female mice to chronic unpredictable stress during adolescence. We then measured locomotor sensitization to repeated nicotine injections in the subsequent F2 and F3 generations. Stress exposure alone (F1) did not influence locomotor sensitization in any lineage. However, in the F1 male lineage, F0 nicotine exposure abrogated locomotor sensitization in F2 male and transiently enhanced locomotor sensitization in F2 female offspring. These effects were not passed down to the F3 generations or observed in the F1 female lineage. F1 stress exposure modulated the effects of prior F0 nicotine exposure in a sex-dependent manner. Specifically, stress blunted the nicotine-induced enhancement in locomotor sensitization observed in F2 female offspring of F1 males. The effect of F0 nicotine and F1 stress exposure in females appears to have skipped a generation and enhanced nicotine sensitization only in the F3 generation, and only in females. This novel multigenerational exposure paradigm examining the inheritance of two different environmental exposures demonstrates that nicotine responses can be modified by nicotine and stress exposure from previous generations, and these effects are strongly influenced by sex.

Cigarette smoking and resultant nicotine dependence remain major public health problems. Most smokers begin before the age of 18, yet preclinical models have insufficiently characterized the development of nicotine dependence in adolescence. To categorize the short-term effects of chronic nicotine administration throughout adolescence and adulthood, we exposed male Sprague Dawley rats to 14 days of continuously delivered nicotine (0, 1.2 or 4.8 mg/kg/d) using a subcutaneous osmotic minipump, starting between postnatal day 33 (p33) and p96. Next, to explore the effects of extended exposure to chronic nicotine, we exposed male Sprague Dawley rats to 42 days of continuous nicotine starting in adolescence (p33) or early adulthood (p68). Somatic and affective signs of precipitated withdrawal (PW) were observed after a mecamylamine (1.5 mg/kg, i.p.) challenge as compared to a saline injection. Short term nicotine exposure starting at p96, well within the adult period, elicited a significant increase in somatic PW as measured by a composite behavioral score. In contrast, adolescent exposure to nicotine elicited a unique behavioral profile, dependent on the starting age of exposure. Late adolescence exposure was characterized by scratching while adult exposure was characterized by facial tremors and yawns. Extended exposure to nicotine resulted in age specific characteristic nicotine withdrawal behaviors, including scratches, ptosis and locomotion, distinct from the short-term exposure. Thus, nicotine dependence severity, based on the expression of total somatic PW behaviors, is not observed until the adult period, and differences between adolescents and adults are observed using a more nuanced behavioral scoring approach. We conclude that age of nicotine initiation affects somatic withdrawal signs and their magnitude. These data serve as a foundation for understanding the underlying brain mechanisms of nicotine dependence and their development over adolescence and early adulthood.

Alcohol is the most commonly used drug in the United States and alcohol abuse can lead to alcohol use disorder. Alcohol use disorder is a persistent condition and relapse rates following successful remission are high. Many factors have been associated with relapse for alcohol use disorder, but identification of these factors has not been well translated into preventative utility. One potentially important factor, concurrent nicotine use, has not been well investigated as a causal factor in relapse for alcohol use disorder. Nicotine increases the value of other stimuli in the environment and may increase the value of alcohol. If nicotine increases the value of alcohol, then nicotine use during and after treatment may make relapse more probable. In the current study, we investigated the effect of continuous nicotine exposure (using osmotic minipumps to deliver nicotine or saline, depending on group, at a constant rate for 28 days) on resurgence of alcohol seeking in rats. Resurgence is a type of relapse preparation that consists of three phases: Baseline, Alternative Reinforcement, and Resurgence Testing. During Baseline, target responses produced a dipper of alcohol. During Alternative Reinforcement, target responses were extinguished and responses on a chain produced a chocolate pellet. During Resurgence Testing, responses on the chain were also extinguished and a return to responding on the target lever was indicative of resurgence. Multilevel modeling was used to analyze the effect of nicotine on resurgence. Both the nicotine and saline group showed resurgence of alcohol seeking, but there was no difference in the degree of resurgence across groups. Future directions could involve testing alternative drug delivery techniques.

Introduction Liquid nicotine exposure is becoming more common in the pediatric population. Toxicity may occur with exposure to small quantities given the high concentrations in solutions available commercially. Effects can include altered mental status, seizure, and death. Methods This simulation-based case involves the identification and management of a toddler presenting with acute liquid nicotine exposure, with emphasis on the general approach to the acutely ill pediatric patient, consideration in toxic exposures, and the presentation of nicotine exposure. Providers should assess airway, breathing, and circulation while concurrently providing supportive care for an actively seizing simulated patient, necessitating appropriate selection of medications and acute airway management. Additionally, providers must maintain a broad differential diagnosis and obtain a focused history to narrow that differential and identify toxic exposure as a cause of the patient's presentation. Preparatory and didactic material is provided to help the instructor prepare the simulation environment, guide learners through the case, and debrief with learners afterward. Results We implemented this curriculum with four pediatric emergency medicine fellows and 15 pediatric residents during two sessions. Feedback was overwhelmingly positive; participants who completed evaluations reported high levels of confidence with knowledge and skills directly related to the educational objectives after participation (mean Likert scores of 4.9 out of 5 in response to effectiveness of the case in teaching evaluation and management of nicotine toxicity). Discussion This comprehensive resource will aid in offering continuing education for providers and specifically in educating learners with regard to acute liquid nicotine exposure in a child.

BACKGROUND AND OBJECTIVES: Although prenatal alcohol and nicotine exposure are associated with reduced cognition in children, associations between consumption of alcohol during lactation and cognition have not been examined. We aimed to examine whether drinking or smoking while breastfeeding lowers children’s cognitive scores. We hypothesized that increased drinking or smoking would be associated with dose-dependent cognitive reductions. METHODS: Data were sourced from Growing Up in Australia: The Longitudinal Study of Australian Children. Participants were 5107 Australian infants recruited in 2004 and assessed every 2 years. Multivariable linear regression analyses assessed relationships between drinking and smoking habits of breastfeeding mothers and children’s Matrix Reasoning, Peabody Picture Vocabulary Test–Third Edition and Who Am I? scores at later waves. RESULTS: Increased or riskier wave 1 maternal alcohol consumption was associated with reductions in Matrix Reasoning scores at age 6 to 7 years in children who had been breastfed (B = −0.11; SE = 0.03; 95% confidence interval: −0.18 to −0.04; P = .01). This relationship was not evident in infants who had never breastfed (B = −0.02; SE = 0.10; 95% confidence interval = −0.20 to 0.17; P = .87). Smoking during lactation was not associated with any outcome variable. CONCLUSIONS: Exposing infants to alcohol through breastmilk may cause dose-dependent reductions in their cognitive abilities. This reduction was observed at age 6 to 7 years but was not sustained at age 10 to 11 years. Although the relationship is small, it may be clinically significant when mothers consume alcohol regularly or binge drink. Further analyses will assess relationships between alcohol consumption or tobacco smoking during lactation and academic, developmental, physical, and behavioral outcomes in children.

Smokers that begin during adolescence are more likely to develop nicotine dependence than those who begin as adults. However, the factors that contribute to this remain largely unknown. Here we utilized a novel operant oral nicotine self-administration procedure in mice to assess the consequences of adolescent nicotine exposure on nicotine and saccharin (non-drug) reinforcement in adults. Animals were given non-contingent exposure to either saline or nicotine using the osmotic minipumps during both adolescence and adulthood for 2 weeks. Reinforcing efficacy for oral nicotine and saccharin was assessed using the progressive ratio schedule 2-weeks following the washout period in adults. Non-contingent nicotine exposure in adolescence drastically increased operant responding for oral nicotine but reduced responding for oral saccharin in the group re-exposed to nicotine in adulthood. Interestingly, adolescent nicotine-exposed mice that received saline exposure as adults exhibited higher preference for oral saccharin. However, breakpoints for oral nicotine in these mice remained comparable to control animals. Surprisingly, both adolescent and adult nicotine exposure increased inactive lever responding during self-administration presumably reflecting impulsive responding. Our data suggest that adolescent nicotine exposure produces an increase in reinforcement sensitivity in adulthood as reflected by increased saccharin self-administration but this sensitivity becomes biased towards nicotine self-administration when re-exposed to nicotine in adulthood. Moreover, nicotine/saccharin reinforcement could be impacted by changes in cognitive control, such as increased impulsivity. These distinct behavioral mechanisms may act in concert to facilitate maladaptive nicotine taking in smokers that initiate nicotine use during adolescence.

Bony complications of diabetes mellitus (DM) are still insufficiently understood. Our aims were to analyze the individual and combined effects of chronic hyperglycemia and nicotine exposure on the femoral trabecular and cortical microarchitecture on a rat experimental model.The micro-computed tomography based bone microstructural evaluation was performed on male Wistar rats divided into four groups: control (n = 7), experimentally-induced DM (n = 8), chronically exposed to nicotine (n = 9) and the DM group exposed chronically to nicotine (n = 9).Chronic hyperglycemia caused mild trabecular deterioration; yet, the combination of hyperglycemia and nicotine exposure showed more deleterious effects on the trabecular bone. Namely, the DM + nicotine group had significantly lower bone volume fraction, fewer and more rod-like shaped trabeculae, along with higher trabecular separation and lower connectivity than the control group (p 0.05). Nicotine alone did not show any significant deterioration compared to the control group. DM and DM + nicotine groups had lower cortical porosity than control and nicotine groups (p 0.05). Cortical thickness did not show any significant intergroup differences, whereas bone perimeter and the mean polar moment of inertia were reduced in DM + nicotine group.Mild effects of chronic hyperglycemia on bone structure were accentuated by the chronic nicotine exposure, although nicotine alone did not cause any significant bone changes. That suggests a synergistic effect of hyperglycemia and nicotine on bone deterioration and increased propensity to fracture. Indeed, better understanding of risk factors driving bone structural deterioration is a precondition to limit the complications associated with DM.

Although e-cigarette use among US youth decreased in 2016 for the first time since 2011,1 2 with the introduction of the new generation of nicotine vapourisers, ‘pods,’ this trend may not continue. Pods are compact, lightweight, ultraportable and easy to use inconspicuously. Popularity of these devices has increased in the past year, most notably, one brand, Juul. Use of Juul and similar products (‘ juuling ’) among youth has parents, teachers and the lay public appropriately concerned. However, to date, there are no data on nicotine exposure among youth who use pod systems. ### Survey To characterise the use of pods among adolescents, we surveyed patients 12–21 years seen at three Stony Brook Children’s Hospital outpatient clinics (Long Island, New York) from April 2017 to April 2018. All participants/parents provided written consent. Participants completed a 60-item anonymous questionnaire about personal use of e-cigarettes, including specific product types and brands, and provided a spot urine sample. ### Product analysis Using previously described analytical methods,3 we measured total nicotine concentration in pod products, purchased online, that were popular among our participants. We also measured total nicotine yields in aerosols generated from these products using a smoking machine and standardised laboratory puffing protocol (70 mL puff volume, 2 s puff duration and puff intervals of 10 s).3 We used gas chromatography-mass …

OBJECTIVES: To investigate exposures to liquid nicotine (including electronic cigarette devices and liquids) among children METHODS: Liquid nicotine exposure data from the National Poison Data System for January 2012 through April 2017 were analyzed. RESULTS: There were 8269 liquid nicotine exposures among children CONCLUSIONS: Pediatric exposures to liquid nicotine have decreased since January 2015, which may, in part, be attributable to legislation requiring child-resistant packaging and greater public awareness of risks associated with electronic cigarette products. Liquid nicotine continues to pose a serious risk for young children. Additional regulation of these products is warranted.