Cited by 178Smoking Behavior and CessationNicotinic Acetylcholine Receptors StudyPrenatal Substance Exposure Effects

Unique, long-term effects of nicotine on adolescent brain.

Open access
Leslie, Frances M.·2020·Pharmacology, Biochemistry, and Behavior

Abstract

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.

Integrity signals

Registry

Crossref · 10.1016/j.pbb.2020.173010

Cites

159 of 159 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

60 of 142 cited sources checked · 31 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Marketing of e-cigarettes to adolescents has been very effective.

    “Marketing of e-cigarettes to adolescents has been very effective (Marynak et al., 2018)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Marynak et al., 2018 source

      The Discussion reports that four in five U.S. youths were exposed to e-cigarette advertising in 2016 and notes an association between advertising exposure and e-cigarette use. It does not establish that marketing caused adolescents to use e-cigarettes or otherwise measure how effective the marketing was. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingcitation

    Nearly 1 million of these students vape daily.

    “Of these, nearly 1 million are vaping daily.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Cullen et al., 2019 source

      The table in the Discussion estimates 3.64 million current e-cigarette users among middle and high school students, but the paper defines current use as use on at least one day in the preceding 30 days. A search for daily or every-day vaping found no estimate of how many students vape daily, so the nearly 1 million figure cannot be verified from our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    Serotonin systems are uniquely sensitive to nicotine during adolescence.

    “Serotonin systems are also uniquely sensitive to nicotine during adolescence (Slotkin & Seidler, 2009; Bang & Commons, 2011; Dao et al., 2011).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Slotkin & Seidler, 2009 source
    • cites Bang & Commons, 2011 source
    • cites Dao et al., 2011 source
      Experimental — accuracy not yet measured
  • Interpretationcitation

    The tolerance of adolescents to nicotine aversion may reflect late maturation of the medial habenula to lateral dorsal tegmental pathway that underlies nicotine aversion.

    “This may reflect late maturation of the medial habenula to lateral dorsal tegmental pathway that underlies nicotine aversion (Wolfman et al., 2018).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Wolfman et al., 2018 source
  • Premisecitation

    Nicotine-induced neuronal activation, measured by immediate early gene expression, is enhanced during adolescence in several limbic regions, including nucleus accumbens shell, basolateral amygdala, VTA, and medial prefrontal cortex.

    “Nicotine-induced neuronal activation, as measured by immediate early gene expression, is also enhanced during adolescence in several limbic regions, including nucleus accumbens shell, basolateral amygdala, VTA and medial prefrontal cortex (Schochet et al., 2005; Shram et al., 2007; Dao et al., 2011).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Schochet et al., 2005 source
    • cites Shram et al., 2007 source
    • cites Dao et al., 2011 source

      The ‘Acute and Subchronic Nicotine Treatment Induces Age-dependent Neural Activation’ section reports greater nicotine-induced c-fos expression in adolescent rats’ nucleus accumbens shell and basolateral amygdala. It reports no significant acute nicotine effect in the prefrontal cortex, and the supplied passages do not establish comparable immediate-early-gene activation in the VTA. Those regions may be covered by the sentence’s other citations, but Dao et al. supports only part of the list. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • May combine two claims. 47
  • Classified as probably not a substantial claim. 4
  • The quote only partly states this claim. 1
  • May combine two claims.

    Findingcitation

    E-cigarette use was almost as prevalent among 10th graders, and 8th graders showed a 157% increase in 30-day e-cigarette use over the last two years.

    “Use of e-cigarettes was almost as prevalent among 10th graders, and was particularly troubling among 8th graders who showed a 157% increase in 30-day e-cigarette use over the last two years.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Miech et al., 2019 source

      The ‘To the Editor’ results report increased nicotine vaping among both 10th- and 8th-graders from 2017 to 2018. They give an 8th-grade increase of 2.6 percentage points over one year, not a 157% increase over two years, and do not establish that use among 10th-graders was almost as prevalent as among 12th-graders. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    About 5 million students in grades 6-12 used e-cigarettes within the past 30 days, up from about 3.6 million in 2018.

    “In absolute numbers, the National Youth Tobacco Survey shows that ~5 million students in grades 6–12 have tried e-cigarettes within the past 30 days, an increase from ~3.6 million in 2018 (Cullen et al., 2019).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Cullen et al., 2019 source

      The 2018 NYTS table (Discussion) estimates 3.64 million current e-cigarette users among middle and high school students, supporting the comparison figure. It estimates 4.92 million current users of any tobacco product—not e-cigarettes—and the paper covers data only through 2018, so it does not support the claimed increase to about 5 million e-cigarette users. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims.

    Findingcitation

    In 2019, 25.4% of 12th graders used e-cigarettes within the last 30 days, an increase of 131% from two years earlier.

    “According to Monitoring the Future survey data (Miech et al., 2019), 25.4% of 12th graders in 2019 used e-cigarettes within the last thirty days, an increase of 131% from two years previously”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Miech et al., 2019 source

      The To the Editor section reports Monitoring the Future data showing an increase in nicotine vaping among 12th graders from 2017 to 2018. It does not report 2019 use, a 25.4% prevalence, or a 131% increase over two years; those specifics are not supported by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims.

    Premisecitation

    In recent years, cigarette use among teenagers has declined while nicotine vaping has increased substantially.

    “Although there has been a decline in teen use of cigarettes in recent years, there has been a huge increase in nicotine vaping.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Cullen et al., 2019 source

      The Abstract (page unavailable) reports decreased menthol-cigarette use and increased flavored e-cigarette use among high school tobacco-product users from 2014 to 2018. It does not establish a decline in cigarette use generally or a huge increase in nicotine vaping among teenagers; the reported high-school flavored e-cigarette measure rose from 65.1% to 67.8%, and the middle-school measure was comparable in 2014 and 2018. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Miech et al., 2019 source

      The To the Editor section reports a sharp increase in nicotine vaping from 2017 to 2018. It also says use of each of six other nicotine products declined in a sample of 12th-graders, but those declines were not statistically significant; it does not establish a broader, multi-year decline in cigarette use among teenagers. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims.

    Premisecitation

    E-cigarettes were introduced to the US market in 2007 and are now the most commonly used tobacco product among teenagers.

    “Although introduced as recently as 2007 to the US market, e-cigarettes are now the most commonly used tobacco product among teenagers (Miech et al., 2017; Wang et al., 2019).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Miech et al., 2017 source

      The Introduction reports rapid growth in e-cigarette use among U.S. students, and the Results say recent vaping was about 50% more prevalent than recent cigarette smoking in the study sample. Neither passage establishes that e-cigarettes were introduced to the U.S. market in 2007 or that they were the most commonly used tobacco product among teenagers overall. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Wang et al., 2019 source

      The Abstract (Results) and Results (Current Tobacco Product Use) identify e-cigarettes as the most commonly used tobacco product among U.S. middle and high school students in 2019. Our copy does not state that e-cigarettes entered the U.S. market in 2007; searches for that date and market introduction found no supporting passage. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the United States, tobacco cigarette use has declined in recent years while e-cigarette use has increased exponentially.

    “Whereas the use of tobacco cigarettes has declined in the United States within recent years, the use of electronic cigarettes (e-cigarettes) has increased exponentially (Cullen et al., 2019; Miech et al., 2019).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Cullen et al., 2019 source

      The Abstract (page unavailable) reports that, among U.S. high school tobacco-product users, menthol cigarette use decreased and flavored e-cigarette use increased during 2014–2018. It does not establish a decline in cigarette use or an exponential increase in e-cigarette use across the United States generally; the reported e-cigarette increase was from 65.1% to 67.8% in that subgroup. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Miech et al., 2019 source

      In “TO THE EDITOR” (page unavailable), the paper reports a sharp rise in nicotine vaping among U.S. adolescents from 2017 to 2018 and says use of six other nicotine products declined, though not significantly. It does not establish exponential growth or a decline in cigarette use across the U.S. population as a whole. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims.

    Premisecitation

    E-cigarettes have been insufficiently regulated and have been readily available to minors in some states.

    “To date there has been insufficient regulation of these potentially dangerous tobacco products and, as a result, they have been readily available to minors in some states (Paradise, 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Paradise, 2014 source
  • May combine two claims.

    Premisecitation

    Adult female rats show less aversion to nicotine than adult males or ovariectomized females, suggesting that ovarian hormones protect against this effect.

    “Adult female rats show less aversion to nicotine than do adult males or oviarectomized females, suggesting that ovarian hormones protect against this effect (Torres et al, 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Torres et al, 2009 source
  • May combine two claims.

    Premisecitation

    Nicotine acts through nicotinic cholinergic receptors, which are pentameric ligand-gated ion channels widely distributed throughout the brain.

    “Nicotine mediates its effects via nicotinic cholinergic receptors (nAChRs), pentameric ligand-gated ion channels that are widely distributed throughout the brain (Dani, 2015; Zoli et al., 2015).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Dani, 2015 source
    • cites Zoli et al., 2015 source
  • May combine two claims.

    Premisecitation

    This nicotine treatment does not affect presynaptic dopamine markers but increases the efficacy of striatal D2 dopamine receptors.

    “Although presynaptic dopamine markers are not impacted by this nicotine treatment, there is an increase in the efficacy of striatal D2 dopamine receptors (Mojica et al., 2014; Linker et al., 2020).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Mojica et al., 2014 source
    • cites Linker et al., 2020 source

      The Results section on D2 receptors states that receptor signaling increases after adolescent nicotine exposure, supporting the D2-efficacy part of the claim. The paper does not establish that presynaptic dopamine markers are unaffected; its Results and Discussion instead report decreases in the presynaptic markers synaptophysin and VGlut2, which are not identified as dopamine markers. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • May combine two claims.

    Premisecitation

    Nicotine is metabolized faster in rodents during pre-adolescence (P23-25) than in adults, producing lower blood levels, but no pharmacokinetic differences are seen during the adolescent period starting at P28.

    “Although nicotine is more rapidly metabolized in rodents during pre-adolescence (P23–25) than in adults, leading to lower blood levels, no pharmacokinetic differences have been seen during the adolescent period starting at P28 (Portugal et al., 2012; Ahsan et al., 2014; Craig et al., 2014; Arany et al., 2017).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Portugal et al., 2012 source

      Results §3.4 finds no difference in plasma nicotine levels among pre-adolescent, adolescent, and adult mice after acute or chronic treatment; the Discussion likewise reports no age-related difference in nicotine metabolism. This contradicts the claimed faster metabolism and lower blood nicotine levels in pre-adolescents. The absence of a detected difference between adolescents and adults is supported, but Methods §2.1 places the adolescent group at PND 38 at the start of experiments, not P28. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Ahsan et al., 2014 source

      The Results section on blood nicotine levels reports concentrations after doses that produced place preference or self-administration, but does not compare nicotine metabolism or blood levels across ages. The Methods and Discussion likewise do not address faster metabolism at P23–25 or the absence of pharmacokinetic differences from P28; searches for those terms and age-related blood-level differences found no supporting passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites Craig et al., 2014 source

      The Abstract and Results report lower plasma nicotine levels and faster nicotine clearance in early-adolescent rats at postnatal day 25 than in adults. The Discussion does not support the more specific claim that faster metabolism caused the lower levels; it points primarily to clearance and distribution and does not find faster conversion to cotinine. The paper compares day-25 rats with adults, so it does not establish that pharmacokinetic differences disappear starting at day 28. Page numbers were unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims.

    Premisecitation

    nAChRs are expressed early in brain development and play critical maturational roles at many stages, including adolescence.

    “nAChRs are expressed early in brain development and play critical maturational roles at many developmental stages, including adolescence (reviewed by Dwyer et al., 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Dwyer et al., 2009 source
  • May combine two claims.

    Premisecitation

    Adolescent males show a strong anxiolytic response to nicotine that diminishes with age, whereas adolescent females show much lower anxiolytic or outright anxiogenic responses depending on the behavioral test.

    “Adolescent males have been shown to have a strong anxiolytic response to nicotine treatment which diminishes with age, whereas adolescent females have much lower anxiolytic or outright anxiogenic responses depending on the behavioral test (Elliott et al., 2004; Cao et al., 2010).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Elliott et al., 2004 source
    • cites Cao et al., 2010 source
  • May combine two claims.

    Premisecitation

    Adolescent mice showed learning enhancement only at the highest nicotine dose, whereas adult mice showed behavioral effects at lower doses.

    “Whereas adolescent mice only showed learning enhancement at the highest nicotine dose, adult mice exhibited behavioral effects at lower nicotine doses.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kutlu et al., 2016 source
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Tobacco constituents, which have been shown to enhance reinstatement of nicotine-seeking behavior, may increase withdrawal signs.

    “Alternatively, tobacco constituents, which have been shown to enhance reinstatement of nicotine seeking behavior (Costello et al., 2014; Cross et al., 2020), may increase withdrawal signs.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Costello et al., 2014 source
    • cites Cross et al., 2020 source
  • May combine two claims.

    Findingcitation

    Although these findings may suggest that adolescent females find nicotine and tobacco more rewarding than males, recent data on middle and high school students show few sex differences in tobacco product use rates, with males showing slightly elevated consumption.

    “Although these findings may suggest that adolescent females find nicotine and tobacco more rewarding than males, recent data on middle and high school students suggest few sex differences in rates of tobacco product use, with males showing slightly elevated consumption (Wang et al., 2019).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wang et al., 2019 source
  • May combine two claims.

    Premisecitation

    Research on e-cigarette withdrawal is limited, but recent analysis of the US Population Assessment of Tobacco and Health Survey and a clinical trial indicated that withdrawal symptoms were mild in never smokers.

    “There is limited research on withdrawal from e-cigarettes, but recent analysis of the US Population Assessment of Tobacco and Health Survey and a clinical trial by the same investgators indicated that withdrawal symptoms were mild in never smokers (Hughes & Callas, 2019; Hughes et al., 2020)”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Hughes & Callas, 2019 source
    • cites Hughes et al., 2020 source
  • May combine two claims.

    Premisecitation

    Two studies using an inhalation method for tobacco smoke or nicotine noted substantial physical withdrawal in adolescents, although adults were not included for comparison.

    “Two studies in which an inhalation method for tobacco smoke or nicotine was used did note substantial physical withdrawal in adolescents, although adults were not included for comparison (de la Pena, 2015; Kallupi et al., 2019).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites de la Pena, 2015 source
    • cites Kallupi et al., 2019 source
  • May combine two claims.

    Premisecitation

    Adolescent nicotine exposure increases later nicotine reward and reduces nicotine aversion in adult animals.

    “Adolescent nicotine treatment increases subsequent nicotine reward and decreases aversion in adults”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Adriani et al., 2003 source

      The Results report that nicotine pretreatment during periadolescence increased nicotine self-administration in adult rats, and the Discussion interprets this as greater sensitivity to nicotine’s reinforcing effects. Our copy does not report reduced nicotine aversion; searches for aversion and aversive effects did not find support for that part of the claim. No page numbers were available in the indexed passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Torres et al., 2008 source

      The Discussion reports that adult rats exposed to nicotine during adolescence did not show the aversion seen at the highest dose in naïve adults. But it also says those rats did not show increased nicotine reward: their dose-response curve was relatively flat, and adolescent exposure did not facilitate conditioned place preference in adulthood. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites Kallupi et al., 2019 source

      The Discussion (page unavailable) reports that high-dose adolescent nicotine-vapor exposure facilitated nicotine self-administration in adult rats. It suggests increased positive reinforcement as one possible explanation, but also offers withdrawal-related reinforcement; it does not establish increased nicotine reward or decreased nicotine aversion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims. The quote only partly states this claim.

    Findingcitation

    In Sprague Dawley rats, once-daily low-dose nicotine (0.06 mg/kg, i.v.) for four days, intended to mimic early teen smoking, enhances subsequent reinforcing effects of cocaine, methamphetamine, and alcohol in adolescents but not adults of both sexes.

    “we have used a paradigm in which Sprague Dawley rats are treated once daily for four days with a low dose of nicotine (0.06 mg/kg, i.v.), intended to mimic the early phase of teen smoking, and have shown this enhances subsequent reinforcing effects of cocaine, methamphetamine and alcohol”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites McQown et al., 2007

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Dao et al., 2011 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
  • May combine two claims.

    Premisecitation

    Microglial activation selectively prunes glutamate synapses in the nucleus accumbens and basolateral amygdala and increases cocaine self-administration.

    “Microglial activation then selectively prunes glutamate synapses in the nucleus accumbens and basolateral amygdala, and results in increased cocaine self-administration.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Linker et al., 2020 source

      The Results section on synaptophysin reports a microglia-dependent decrease in a presynaptic marker in the nucleus accumbens after adolescent nicotine exposure; VGlut2 decreased while VGlut1 did not. The Results section on cocaine self-administration reports that suppressing or eliminating microglia blocked nicotine-induced increases in cocaine reinforcement. The paper does not show selective pruning of glutamate synapses in both the nucleus accumbens and basolateral amygdala: its synaptic-marker findings concern the nucleus accumbens, and decreased marker levels are not direct evidence of pruning. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims.

    Findingcitation

    Adolescents who use flavorants are often unaware of their nicotine exposure; in one study, 40% of subjects with significant urinary cotinine reported using only nicotine-free products.

    “Adolescents who use flavorants are also frequently unaware of their nicotine exposure, with 40% of subjects with significant urinary cotinine in a recent study reporting that they used only nicotine-free products (Boykan et al., 2019b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Boykan et al., 2019b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation

    Adolescents who used e-cigarettes with non-traditional flavors were more likely to continue vaping and to take more puffs per session six months later.

    “Furthermore, adolescents who used e-cigarettes with non-traditional flavors are more likely to continue vaping and take more puffs per session six months later (Leventhal et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Leventhal et al., 2019 source
  • May combine two claims.

    Findingcitation

    Adriani and colleagues found no sex differences in this effect, but most other studies have not compared sex and age differences within the same study to allow direct comparison of males and females.

    “Whereas Adriani and colleagues found no sex differences in this effect, most other studies have not compared sex and age differences within the same study to allow a direct comparison of males and females.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Findingown data

    In an intravenous self-administration paradigm, nicotine combined with alcohol is self-administered at much higher rates in male adolescents than in adults, and with much greater alcohol intake in adolescents than alcohol alone.

    “Using an intravenous self-administration paradigm, we have shown that nicotine combined with alcohol is self-administered at much higher rates in male adolescents than adults, and with much greater alcohol intake in adolescents than that of alcohol alone (Figure 2A).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingnone given

    These withdrawal signs are routinely seen in adult rodents but not in adolescents.

    “Although these withdrawal signs are routinely seen in adult rodents, this is not the case for adolescents.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Premisecitation

    Flavorants can produce different patterns of nicotine delivery and reduce perceived risk.

    “Flavorants can lead to different patterns of nicotine delivery and a decreased perception of risk (Voos et al., 2019; Jensenn and Boykan, 2019; Boccio et al., 2020).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Voos et al., 2019

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Jensenn and Boykan, 2019

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Boccio et al., 2020 source
  • May combine two claims.

    Premisecitation

    Adolescents of both sexes are more sensitive than adults to the rewarding effects of nicotine in conditioned place preference tests, with some studies showing reward after a single drug-context pairing.

    “Adolescents of both sexes are more sensitive than adults to the rewarding effects of nicotine, as shown in conditioned place preference tests (Vastola et al., 2002; Shram et al., 2006; Kota et al., 2007; Torres et al., 2008; Ahsan et al., 2014; Lenoir et al., 2015), with some studies demonstrating reward after a single pairing of drug and context (Belluzzi et al., 2004; Brielmaier et al., 2007).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Vastola et al., 2002 source
    • cites Shram et al., 2006 source
    • cites Kota et al., 2007 source
  • May combine two claims.

    Interpretationreasoning

    Nicotine is a neurotoxicant that can produce unique and long-lasting negative behavioral effects in adolescents.

    “However, as has been particularly highlighted in pre-clinical studies, described below, nicotine is a neurotoxicant that can produce unique and long-lasting negative behavioral effects in adolescents.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models of adolescent nicotine exposure can be generalized to humans.
  • May combine two claims.

    Premisecitation

    In one recent study measuring reward by reduction in brain reward thresholds, adult males and females showed no sex difference in nicotine reward, whereas adolescent females (P40-59) were significantly more sensitive to nicotine reward than adolescent males.

    “However, in one recent study in which reward was measured by reduction in brain reward thresholds, there was no sex difference in the rewarding effects of nicotine in adults, whereas adolescent females (P40–59) were significantly more sensitive to the rewarding effect of nicotine than their male counterparts (Xue et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xue et al., 2020 source
  • May combine two claims.

    Premisecitation

    Nicotine-stimulated dopamine release from ventral striatal slices is age- and sex-dependent, highest in male rats during early adolescence (P30), with no significant age differences in females.

    “Nicotine-stimulated dopamine release from ventral striatal slices shows complex age- and sex-dependence, being highest in male rats during early adolescence (postnatal day (P)30), with females showing no significant age differences (Azam et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Azam et al., 2007 source
  • May combine two claims.

    Premisecitation

    Nicotine inhibits locomotor activity in late adolescence and adulthood, but in early adolescence it either has no effect or stimulates motor activity.

    “Whereas nicotine inhibits locomotor activity in late adolescence and adulthood, it either has no effect (Lopez et al., 2003; Belluzzi et al., 2004; Miller et al., 2019) or stimulates motor activity in early adolescence (Adriani et al., 2002; Cao et al., 2010).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lopez et al., 2003 source
    • cites Belluzzi et al., 2004 source
    • cites Miller et al., 2019 source
  • May combine two claims.

    Interpretationreasoning

    Low perceived health risk, appealing flavors, and minimal market regulation have created conditions for wide e-cigarette use among adolescents.

    “The perceptions of low health risk, combined with the appeal of flavors and minimal market regulations, have created a climate for the wide use of e-cigarettes among adolescents.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Premisecitation

    Adults of both sexes experience aversive effects from high doses of nicotine, whereas adolescents tolerate the drug well.

    “Whereas adults of both sexes experience aversive effects of high doses of nicotine, adolescents tolerate the drug well (Adriani et al., 2002; Shram et al., 2006; Torres et al., 2008, 2009; Lenoir et al., 2015).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Adriani et al., 2002 source
    • cites Shram et al., 2006 source
    • cites Torres et al., 2008, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationnone given

    Most studies show age differences in the acute in vivo effects of nicotine, but the pattern of these differences is not consistent.

    “Whereas most studies have shown age differences in the acute in vivo effects of nicotine, there is no consistent pattern to these findings.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Premisecitation

    Early-adolescent DBA/2J mice were insensitive to nicotine-induced hypothermia while C57BL/6J mice were sensitive at that age; both strains became more sensitive as development progressed.

    “Strain differences were observed in which early-adolescent mice of the DBA/2J strain were insensitive to nicotine-induced hypothermia, whereas C57BL/ 6J were sensitive at this age. However, both strains showed increased sensitivity to nicotine as development progressed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miller et al. (2019) source
  • May combine two claims.

    Premisecitation

    Late-adolescent animals show the same inhibitory locomotor response to acute nicotine as adults but greater locomotor sensitization to repeated nicotine treatment.

    “Although animals in late adolescence exhibit the same inhibitory locomotor response to acute nicotine as adults, they show greater locomotor sensitization to repeated nicotine treatment (Belluzzi et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Belluzzi et al., 2004 source
  • May combine two claims.

    Interpretationcitation

    Despite one group arguing against a biological vulnerability of adolescents to nicotine, most studies show that adolescent rats readily acquire intravenous nicotine self-administration and have higher drug intake than adults.

    “Although one group has argued against a biological vulnerability of adolescents to nicotine (Shram et al., 2008), the majority of studies have shown that adolescent rats readily acquire intravenous nicotine self-administration and have higher drug intake than adults (Chen et al., 2007; Levin et al. 2003, 2007; Natividad et al., 2013: Ahsan et al., 2014; Gellner et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Shram et al., 2008 source
    • cites Chen et al., 2007 source
    • cites Levin et al. 2003, 2007

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Strain differences exist in adolescent physical withdrawal signs: Sprague Dawley rats of both sexes show significant withdrawal for two days after nicotine removal, whereas Long Evans rats show shortened (males) or non-existent (females) withdrawal.

    “Strain differences have also been noted in adolescent physical withdrawal signs (Hamilton et al., 2010); whereas Sprague Dawley rats of both sexes were found to show significant withdrawal signs for two days after nicotine removal, Long Evans rats exhibit shortened (males) or non-existent (females) withdrawal.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hamilton et al., 2010 source
  • May combine two claims.

    Premisecitation

    Both sexes found the nicotine-acetaldehyde combination highly rewarding during early adolescence (P27); this reinforcing effect diminished significantly in males at later ages (P34 and adult) but remained high in females.

    “Whereas both sexes found the drug combination to be highly rewarding during early adolescence (P27), this initial reinforcing effect had significantly diminished in males at later ages (P34 and adult), whereas it remained high in females.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Park et al., 2007 source
  • May combine two claims.

    Premisecitation

    Adolescent, but not adult, nicotine downregulates KCC2, shifts EGABA depolarizing, and inhibits ethanol-stimulated dopamine release.

    “Adolescent, but not adult, nicotine downregulated the chloride channel, KCC2, causing a depolarizing shift in EGABA and resulting inhibition of ethanol-stimulated dopamine release.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Thomas et al., 2018 source
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Smoking and drinking are two of the earliest drug use behaviors in human teens, and many reports indicate a positive interaction between smoking and drinking in this age group.

    “Smoking and drinking are two of the earliest drug use behaviors in human teens, and many reports indicate a positive interaction of smoking and drinking in this age group (Dani & Harris, 2005; Kristjansson et al., 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dani & Harris, 2005 source
    • cites Kristjansson et al., 2015 source
  • May combine two claims.

    Premisecitation

    Adult dependent smokers are more likely to be alcoholic than non-smokers, and most alcoholics smoke.

    “Adult dependent smokers are also much more likely to be alcoholics than non-smokers, and the great majority of alcoholics smoke”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites DiFranza & Guerrera, 1990 source
    • cites Falk et al., 2006
  • May combine two claims.

    Premisecitation

    A recent study reported that teen e-cigarette users are more likely to report dependence signs and be daily users if they use high-nicotine-content pods such as Juul.

    “A recent study has reported that teen e-cigarette users are more likely to report dependence signs and be daily users if they use high nicotine content pods, such as Juul (Boykan et al., 2019a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Boykan et al., 2019a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Nicotine treatment of male adolescent rats increases impulsive behavior and decreases attention in adulthood, with no effect in rats treated as adults.

    “Nicotine treatment of male adolescent rats resulted in increased impulsive behavior and decreased attention in adulthood, but had no effect on animals that are treated as adults”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Counotte et al., 2011 source
  • May combine two claims.

    Premisecitation

    In Lewis but not Fischer rats, adolescent nicotine treatment enhances cocaine conditioned place preference and potentiates dopamine response in the nucleus accumbens shell.

    “only Lewis rats show enhancement of cocaine conditioned place preference and a concomitant potentiation of dopamine response in the nucleus accumbens shell following adolescent nicotine treatment”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cadoni et al., 2019

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The enhancement of cocaine intake after adolescent nicotine pretreatment appears immediately and persists into adulthood, but is not seen for sucrose.

    “The enhancement of cocaine intake is seen immediately following nicotine pretreatment and persists through adulthood, but is not seen for sucrose.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Premisecitation

    Adolescent, but not adult, nicotine induces long-term social withdrawal and deficits in social cognition.

    “adolescent, but not adult nicotine, induces long-term social withdrawal and deficits in social cognition”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jobson et al., 2019 source
48 of 48
  • The paper relies on this without support.

    Adolescence is a developmental period of high plasticity in brain systems that control motivated behavior and cognition.

    “Adolescence is a time of major plasticity of brain systems that regulate motivated behavior and cognition”
  • The paper relies on this without support.

    Adolescence is the period when nicotine use most commonly begins.

    “is also the age of peak onset of nicotine use”
  • The paper relies on this without support.

    Findings from animal models of adolescent nicotine exposure can be generalized to humans.

    “This review compares and integrates human and animals findings.”
  • The paper relies on this without support.

    The rodent adolescent period studied corresponds to human adolescence.

    “no pharmacokinetic differences have been seen during the adolescent period starting at P28”
  • The paper relies on this without support.

    Adolescent nicotine exposure causes long-term negative effects on brain and behavior in humans.

    “Given the substantial evidence for long-term negative impact of adolescent nicotine exposure on brain and behavior”
  • The paper relies on this without support.

    Observational human studies can confirm that behavioral effects of adolescent nicotine exposure are similar across species.

    “an emerging observational literature suggests similarities across species”
  • The paper relies on this without support.

    Animal models of adolescent nicotine exposure are informative about human adolescent nicotine effects, including vaping.

    “Given ethical constraints on conducting experimental drug studies on human teens, this necessitates the use of animal studies.”
    “These preclinical findings suggest that teen nicotine vaping may result in similar long-term deleterious effects”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • These findings align with a previous review, which suggested increased anxiety-related behaviour in adolescents, and extend findings by incorporating additional paradigms.

    “These findings align with a previous review, which suggested increased anxiety-related behaviour in adolescents (Leslie, 2020), and extend findings by incorporating additional paradigms that measure different aspects of anxiety-related behaviour.”

    From Age-dependent Effects of Tobacco Smoke and Nicotine on Cognition and the Brain: A Systematic Review of the Human and Animal Literature Comparing Adolescents and Adults. (2023) · cites this paper as Leslie, 2020

    The review’s Emotional regulation section reports that nicotine treatment during adolescence increases anxiety in later life. That supports an association with adolescent nicotine exposure, but not the claim that anxiety-related behaviour is increased during adolescence. Its Acute nicotine effects section also describes an anxiolytic response in adolescent males. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • Clinical studies have shown that nicotine exposure during adolescence, but not adulthood, is associated with subsequent increases in substance use (i.e., "gateway hypothesis").

    “Clinical studies have shown that nicotine exposure during adolescence, but not adulthood, is associated with subsequent increases in substance use (i.e., “gateway hypothesis”) [6,7,105,145].”

    From Nicotine on the developing brain. (2023) · cites this paper as [6]

    In “Chronic effects of adolescent nicotine treatment > Drug reward” (page unavailable), the review reports clinical links between teen smoking and later use of other drugs, including cocaine. It does not report a clinical finding that adolescent exposure, but not adult exposure, predicts subsequent substance use; that age contrast comes from the animal studies it discusses. (LLM, conf=0.87)

    Experimental — accuracy not yet measured
  • Nicotine exposure during this highly plastic state induces long term changes in critical circuitry, maturation of monoamine systems, and behavior, including reward related behaviors.

    “Nicotine exposure during this highly plastic state induces long term changes in critical circuitry, maturation of monoamine systems, and behavior, including reward related behaviors (see Fig. 3) [4,6,7].”

    From Nicotine on the developing brain. (2023) · cites this paper as [6]

    The Conclusions and “Drug reward” sections report long-term changes in brain circuitry and behavior after adolescent nicotine exposure, including increased reward from other drugs. The “Acute neurochemical effects on monoamine systems” and “Drug reward” sections describe changes in serotonin and dopamine signaling, but do not establish that nicotine changes the maturation of those systems. The evidence discussed is principally from animal studies; page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured
  • Adolescent rodents show increased sensitivity to the locomotor activating and rewarding effects of nicotine, blunted withdrawal symptoms, and reduced aversion to high doses of nicotine, compared to adult counterparts.

    “many studies have shown that adolescent rodents show an increased sensitivity to the locomotor activating and rewarding effects of nicotine, blunted withdrawal symptoms, and reduced aversion to high doses of nicotine, compared to adult counterparts.”

    From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [90]

    The “Short-term behavioral effects” section supports greater nicotine reward and reduced aversion to high doses in adolescent rodents, while “Withdrawal syndrome” reports generally lower withdrawal signs than in adults. The locomotor claim needs an age qualifier: nicotine can stimulate activity in early adolescence, but inhibits it in late adolescence as it does in adulthood; late-adolescent rodents instead show greater sensitization after repeated treatment. Page numbers were not supplied. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • Nicotine in adolescence increases later sensitivity to the rewarding effects of nicotine, while decreasing its aversive effects.

    “Nicotine in adolescence has been shown to increase later sensitivity to the rewarding effects of nicotine, while decreasing its aversive effects; these studies have been thoroughly reviewed elsewhere, see: [90, 92]).”

    From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [90]

    The ‘Acute nicotine effects in adolescents—Short-term behavioral effects’ section reports greater nicotine reward and less aversion in adolescent rodents than in adults. It does not establish that nicotine exposure during adolescence causes those responses later in life. The ‘Chronic effects—Drug reward’ section instead describes lasting increases in reward from other drugs. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Cites

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Authors
Leslie, F. M.
Affiliations
University of California, Irvine (US)
Corresponding author
Leslie, Frances M.
Venue
Pharmacology, Biochemistry, and Behavior
Publisher
Elsevier BV
Published
2020-10
Volume
197
Pages
173010
ISSN
0091-3057 (ISSN-L)
OpenAlex
W3045780954
Cited by
178
References
166
Citations by year
2026: 32 · 2025: 33 · 2024: 35 · 2023: 29 · 2022: 35 · 2021: 13 · 2020: 1
FWCI
2.49
Type
journal article
Language
en
Open access
Locations
  • Pharmacology Biochemistry and Behavior (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
Keywords
adolescent nicotine exposure, adolescent brain development, nicotine vaping, electronic cigarettes, age and sex differences, drug reward, drug aversion, cognition, emotions, neurochemistry, human-animal comparison
MeSH terms
Vaping, Adolescent, Age Factors, Animals, Behavior, Animal, Brain, Cognition, Emotions, Female, Humans, Male, Nicotine, Receptors, Nicotinic, Reward, Substance Withdrawal Syndrome, United States, Electronic Nicotine Delivery Systems

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

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