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Cited by 307Smoking Behavior and CessationNicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology Research

Short- and Long-Term Consequences of Nicotine Exposure during Adolescence for Prefrontal Cortex Neuronal Network Function

Open access
Goriounova, N. A., Mansvelder, H. D.·2012·Cold Spring Harbor Perspectives in Medicine
DOI 10.1101/cshperspect.a012120PMC PMC3543069
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Abstract

More than 70% of adolescents report to have smoked a cigarette at least once. At the adolescent stage the brain has not completed its maturation. The prefrontal cortex (PFC), the brain area responsible for executive functions and attention performance, is one of the last brain areas to mature and is still developing during adolescence. Smoking during adolescence increases the risk of developing psychiatric disorders and cognitive impairment in later life. In addition, adolescent smokers suffer from attention deficits, which aggravate with the years of smoking. Recent studies in rodents reveal the molecular changes induced by adolescent nicotine exposure that alter the functioning of synapses in the PFC and that underlie the lasting effects on cognitive function. Here we provide an overview of these recent findings.

Integrity signals

Registry

Crossref · 10.1101/cshperspect.a012120

Cites

139 of 139 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

32 of 147 cited sources checked · 14 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Activation of mGluR2s can inhibit GABA release through a presynaptic mechanism.

    “It was shown that activation of mGluR2s can also regulate release of other neurotransmitters: it can inhibit GABA release via a presynaptic mechanism (Bradley et al. 2000; Pilc et al. 2008).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Bradley et al. 2000 source

      In the section on the presynaptic mechanism (page unavailable), the paper says group II mGluRs likely inhibit glutamate release from presynaptic terminals, not GABA release. Its reference to GABAergic neurons identifies the cells receiving that excitatory input; it does not identify the transmitter being released by the affected terminals. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Pilc et al. 2008 source
  • Interpretationreasoning

    Adolescent brain development may explain characteristic adolescent traits such as mood swings, impulsivity, risk taking, and peer-directed social interactions.

    “Thereby, brain development may be responsible for characteristic adolescent traits—uncontrollable mood swings, impulsivity, risk taking, and peer-directed social interactions (Orr and Ingersoll 1995; Spear 2000; Galvan et al. 2007).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Orr and Ingersoll 1995 source
    • cites Spear 2000 source

      The Introduction (p. 1) proposes that brain maturation contributes to adolescent behavior, and the opening discussion (p. 1) identifies peer-directed interactions and risk taking as characteristic. Section 4.1 (p. 13) reports greater extremes in mood, but our copy does not establish uncontrollable mood swings or impulsivity as characteristic traits explained by brain development. The Summary (p. 31) also cautions that causality cannot be inferred. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Galvan et al. 2007

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

  • Premisecitation

    Laboratory animals also show a difference in nicotine sensitivity between adolescents and adults.

    “The difference in sensitivity to nicotine between adolescents and adults is also reported for laboratory animals (Slotkin 2002; Adriani et al. 2003).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Slotkin 2002 source
    • cites Adriani et al. 2003 source
  • Premisecitation

    Heavy smoking predicts incident cognitive impairment and cognitive decline.

    “heavy smoking predicts incident cognitive impairment and decline (Cervilla et al. 2000; Richards et al. 2003)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Cervilla et al. 2000

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

    • cites Richards et al. 2003 source

      The Abstract and Discussion report that heavy smoking was associated with poorer cognitive performance and faster verbal-memory decline between ages 43 and 53. The paper does not report incident cognitive impairment as a measured outcome; it describes changes in test scores and only suggests a possible risk of clinically significant decline later in life. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The nicotine-induced shift in prefrontal network activity may affect plasticity and refinement of cortical connections.

    “This may affect plasticity and refinement of cortical connections (Couey et al. 2007)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Couey et al. 2007 source

      The Abstract (page not supplied) reports that nicotine raises the threshold for spike-timing-dependent synaptic potentiation in mouse prefrontal cortex, supporting an effect on plasticity. The Discussion describes possible effects on prefrontal network processing, but does not address refinement of cortical connections. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims. 49
  • Classified as probably not a substantial claim. 12
  • Borderline: one of the tests for a substantial claim is unclear. 1

  • May combine two claims.

    Premisecitation

    Smoking by parents, siblings, and friends increases adolescents' risk of smoking, and this social influence decreases with age.

    “The smoking behavior of parents, siblings, and friends leads to a higher risk of smoking among adolescents and this social influence decreases with age (Vink et al. 2003).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Vink et al. 2003 source

      The Age differences section (page not provided) reports higher smoking risk among people with smoking family members or friends in all age groups; the association with smoking mothers, siblings, or friends was stronger at ages 12–15 than at older ages. The study reports associations, not that others’ smoking causes adolescent smoking, and it does not establish that every parental association decreases with age. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Early nicotine exposure during the transition from child to adult may harm by disrupting normal brain maturation and causing lasting effects on cognitive ability, mental health, and personality.

    “Early exposure to nicotine during the transition from child to adult may be harmful, since it may derange the normal course of brain maturation and have lasting consequences for cognitive ability, mental health, and even personality (Brown et al. 1996; Choi et al. 1997; Richards et al. 2003; Brook et al. 2004; Deas 2006).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Brown et al. 1996 source
    • cites Choi et al. 1997 source
    • cites Richards et al. 2003 source

      The Discussion reports an association between cigarette smoking and faster verbal-memory decline from ages 43 to 53, supporting the claim’s cognitive-harm component. The study assessed smoking in adulthood, however; it does not establish that nicotine exposure during the transition to adulthood disrupts brain maturation or causes lasting effects on mental health or personality. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Nicotine is psychoactive and addictive and acts directly on brain regions involved in emotional and cognitive processing.

  • May combine two claims.

    Premisecitation

    Brain development continues through adolescence, with different brain areas maturing at different speeds and times.

    “Brain development continues throughout adolescence, although the speed and timing of maturation varies for different brain areas (Gogtay et al. 2004).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gogtay et al. 2004 source

  • May combine two claims.

    Premisecitation

    Structural and functional MRI data show earlier maturation of reward systems and slower development of prefrontal cognitive control.

    “Structural and functional MRI data show earlier maturation of reward systems and much slower development of prefrontal cognitive control (Spear 2000; Chambers et al. 2003; Casey et al. 2005; Ernst et al. 2005; Ernst and Fudge 2009).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Spear 2000 source

      Section 6.3 (p. 23) describes prefrontal remodeling through adolescence and reports developmental differences in prefrontal activation; it also cites a functional MRI finding of differing amygdala and frontal-lobe activity (p. 24). But the paper does not establish from structural and functional MRI data that reward systems mature earlier than prefrontal cognitive control. Section 6.6.3 (p. 29) cautions that much of the relevant developmental evidence comes from rodents and that imaging these interactions in humans remains challenging. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Chambers et al. 2003 source
    • cites Casey et al. 2005 source

  • May combine two claims.

    Premisecitation

    Compared with adults, adolescents are more motivated by rewards, less averse to risks, and more easily influenced by peers.

    “Compared with adults, adolescents are generally more motivated by rewards, are less averse to risks, and are more easily influenced by peers (Spear 2000; Steinberg 2005; Galvan et al. 2006).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Spear 2000 source

      Section 2.2 (p. 5) reports disproportionate risk-taking among adolescents relative to other ages, and section 2.1 (p. 4) says peer conformity to antisocial behavior peaks in early to mid-adolescence. But section 6.7 (p. 30) tentatively suggests adolescents obtain less positive impact from some rewards and may seek additional reinforcers; it does not establish that they are generally more motivated by rewards than adults. Greater risk-taking also does not, by itself, establish lower aversion to risk. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Steinberg 2005 source
    • cites Galvan et al. 2006

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

  • May combine two claims.

    Premisecitation

    Up-regulation is not accompanied by increased nAChR subunit mRNA; instead it increases nAChR protein levels through increased assembly and/or decreased degradation.

    “Up-regulation is not accompanied by an increase in nAChR subunit mRNA (Marks et al. 1992); instead it leads to increased nAChR protein levels resulting from increased assembly and/or decreased degradation of nAChRs (Marks et al. 2011).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Marks et al. 1992 source
    • cites Marks et al. 2011

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

  • May combine two claims.

    Premisecitation

    Increased inhibition can block long-term potentiation induction in the hippocampus and raise the threshold for spike-timing-dependent plasticity.

    “Increased inhibition can lead to blockade of long-term potentiation (LTP) induction in the hippocampus (Ji et al. 2001) and increase in the threshold for induction of spike-timing-dependent plasticity (STDP) (Couey et al. 2007).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Ji et al. 2001

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

    • cites Couey et al. 2007 source

  • May combine two claims.

    Premisecitation

    Nicotine stabilizes nAChRs during assembly and maturation, most pronounced for the highest-affinity α4β2-containing nAChR.

    “It stabilizes nAChRs during assembly and maturation and this stabilization is most pronounced for the highest-affinity nAChR containing α4β2 subunits.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Lester et al. 2009 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prefrontal mGluR2 signaling is linked to brain disorders such as depression and schizophrenia.

    “the important role of prefrontal mGluR2 signaling in cognition is stressed by its link to brain disorders such as depression and schizophrenia.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Gupta et al. 2005 source

      The Conclusions report increased prefrontal mGluR2/3 protein expression in schizophrenia and suggest that mGluR activity may be altered. The paper does not establish a link with depression, distinguish mGluR2 from mGluR3 in that finding, or test cognition; its reference-list mentions of depression do not support those parts of the claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Palucha and Pilc 2005

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

    • cites Pilc et al. 2008 source

  • May combine two claims.

    Premisecitation

    Layer V pyramidal neurons in PFC receive diverse information from mediodorsal thalamus and local neurons, and these connections are important for executive functions such as working memory.

    “Layer V pyramidal neurons in PFC handle diverse incoming information from mediodorsal thalamus and from local neurons, and these connections are important in mediating executive functions such as, for example, working memory (Floresco et al. 1999).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Floresco et al. 1999 source

      The Discussion reports that inputs from the mediodorsal thalamus converge in the PFC, and the section ‘A distributed circuit for working memory’ links the thalamus–PFC pathway to executive processing during a working-memory task. Our copy does not identify layer V pyramidal neurons as the recipients or describe inputs from local neurons. The indexed passages provide section labels but no page numbers. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    This up-regulation was paralleled by a functional elevation in nicotine-stimulated GABAergic transmission, indicating functional surface nAChRs are up-regulated.

    “This up-regulation was paralleled by a functional elevation in nicotine-stimulated GABAergic transmission, indicating that functional surface nAChRs are up-regulated as well (Counotte et al. 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Counotte et al. 2012

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

  • May combine two claims.

    Findingown data

    Prefrontal cortex layers II-III pyramidal cells do not contain nAChRs, and glutamatergic inputs to these neurons are not modulated by nAChRs.

    “We find that PFC layers II–III pyramidal cells also do not contain nAChRs, and also glutamatergic inputs to these pyramidal neurons are not modulated by nAChRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    These presynaptic mechanisms are specific to layer V, absent in layers II-III, and moderate in layer VI.

    “These presynaptic mechanisms are specific to layer V, as they are absent in layers II–III and moderate in layer VI.”
    Quote in the paperNot a substantial claim

  • Borderline on S3 (load-bearing): unclear from the text.

    Premisecitation

    Repeated nicotine exposure increases dendritic length and spine density in medial PFC neurons.

    “repeated nicotine exposure also changes the structure of neurons in medial PFC: it increases both dendritic length and spine density (Brown and Kolb 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brown and Kolb 2001 source

  • May combine two claims.

    Premisecitation

    Among adolescents, withdrawal symptoms and failed quit attempts can precede daily smoking dependence and appear before consumption reaches two cigarettes per day.

    “Among adolescents the appearance of tobacco withdrawal symptoms and failed attempts to stop smoking can precede daily smoking dependence and appear even before consumption reaches two cigarettes per day (DiFranza et al. 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites DiFranza et al. 2007 source

  • May combine two claims.

    Premisecitation

    Rats first exposed to nicotine during adolescence self-administer more nicotine than rats first exposed in adulthood, and this difference persists into later age.

    “Rats first exposed to nicotine during adolescence self-administer more nicotine than rats exposed in adulthood and these differences in self-administration at first exposure persist into later age (Levin et al. 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Levin et al. 2003 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Risk-taking behavior typical of adolescents is associated with high mortality and morbidity among young people.

    “Indeed, risk-taking behavior, so typical for adolescents, is associated with high rates of mortality and morbidity among young people (Grunbaum et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Grunbaum et al. 2004

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

    Premisecitation

    nAChR subunits assemble in different stoichiometries to form pentameric channels, and subunit compositions vary by brain region.

    “These subunits assemble in different stoichiometries to form pentameric channels, and subunit compositions of nAChRs vary depending on the brain region (for a review, see Grady et al. 2002; Le Novere et al. 2002; McGehee 2002; Alkondon and Albuquerque 2004; Wonnacott et al. 2005; Mineur and Picciotto 2008; Millar and Gotti 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Grady et al. 2002 source
    • cites Le Novere et al. 2002 source
    • cites McGehee 2002 source

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

    Premisecitation

    In 41 European and North American countries, 19% of 15-year-olds smoke at least weekly and 30% tried cigarettes before age 14.

    “According to a recent study conducted in 41 countries in Europe and North America, 19% of 15-year-olds smoke at least once a week and 30% report experimenting with cigarettes before the age of 14 (Currie et al. 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Currie et al. 2008

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

    Premisecitation

    Twelve genes encode neuronal nicotinic receptors; in the central nervous system nine α-subunits and three β-type subunits are expressed.

    “Twelve genes have been identified encoding neuronal nicotinic receptors (for a review, see Le Novere et al. 2002; Millar and Gotti 2009). In the central nervous system nine α-subunits (α2–α10) and three β-type subunits (β2–β4) are expressed.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Le Novere et al. 2002 source
    • cites Millar and Gotti 2009 source

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

    Premisecitation

    Nicotine is distributed quickly through the bloodstream and crosses the blood-brain barrier, reaching the brain within 10-20 seconds after inhalation.

    “Once nicotine has entered the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 sec after inhalation (Le Houezec 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Le Houezec 2003

  • May combine two claims.

    Premisecitation

    Adolescent rats are more sensitive to nicotine-conditioned place preference than adult rats and require lower doses or even a single injection to establish it.

    “Similarly, much lower doses of nicotine or a single injection are sufficient to establish conditioned place preference in adolescent rats, but not in adult animals (Vastola et al. 2002; Belluzzi et al. 2004; Brielmaier et al. 2007).”
    • Also stated in: § UP-REGULATION OF nAChRs AND SYNAPTIC mGluRs IN PREFRONTAL CORTEX BY NICOTINE EXPOSURE DURING ADOLESCENCE · plain
      “Furthermore, adolescent animals are more sensitive to nicotine-conditioned place preference than adults and show this at lower nicotine doses (Vastola et al. 2002; Belluzzi et al. 2004; Shram et al. 2006; Brielmaier et al. 2007; Kota et al. 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Vastola et al. 2002 source
    • cites Belluzzi et al. 2004 source
    • cites Brielmaier et al. 2007 source

  • May combine two claims.

    Interpretationreasoning

    Because nicotine acts directly on cognitive-control pathways, prefrontal cortex development during adolescence may be affected by nicotine exposure.

    “Because nicotine acts directly on the pathways involved in cognitive control, development of the PFC during adolescence may be affected by nicotine exposure.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Nicotine is psychoactive and addictive and acts directly on brain regions involved in emotional and cognitive processing.

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

    Premisecitation

    nAChRs are cation-selective channels that allow Na+, K+, and Ca2+ flow, causing depolarizing currents and neuronal activation.

    “Nicotinic AChRs are cation selective channels that permit the flow of Na+, K+, and Ca2+ across the membrane, which leads to depolarizing currents and activate neurons (McGehee and Role 1995; Millar and Gotti 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites McGehee and Role 1995 source
    • cites Millar and Gotti 2009 source

  • May combine two claims.

    Premisecitation

    These effects are most evident under stressful or emotionally intense states and most pronounced when smoking begins in early adolescence.

    “These effects are particularly evident under stressful or emotionally intense states and are most pronounced when smoking begins during early adolescence (DeBry and Tiffany 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites DeBry and Tiffany 2008 source

  • May combine two claims.

    Interpretationreasoning

    The adolescent brain is more vulnerable to nicotine than the adult brain, likely because of its ongoing development.

    “Taken together, most likely owing to its on-going development, the adolescent brain is more vulnerable to the effects of nicotine than the adult brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Adolescents with ADHD symptoms are more likely to experiment with smoking and become regular tobacco users.

    “Adolescents with ADHD symptoms, whose behavior is even more characterized by impulsive and risk-taking choices, are more likely to experiment with smoking and to become regular tobacco users (Tercyak et al. 2002; McClernon et al. 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Tercyak et al. 2002 source
    • cites McClernon et al. 2008 source

  • May combine two claims.

    Interpretationreasoning

    During adolescence, emotional drive is already strong while cognitive self-control and adult decision-making strategies are still developing.

    “Thus, during adolescence emotional drive has already become very strong, whereas cognitive self-control and adult decision-making strategies still are developing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    mGluR2 receptors sit presynaptically on glutamatergic terminals and, when activated by glutamate spillover, reduce glutamate release.

    “Metabotropic GluR2 receptors are located on presynaptic glutamatergic terminals where they are activated by glutamate spillover to inhibit glutamate release (Mateo and Porter 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mateo and Porter 2007 source

  • May combine two claims.

    Interpretationreasoning

    During chronic nicotine exposure in adolescent PFC, network activity may shift toward deep-layer excitatory neurons while overall inhibition increases.

    “It follows that during chronic nicotine exposure of the adolescent PFC, the pattern of activity in the prefrontal network may gradually shift toward activation of excitatory neurons in deep layers in the context of increased overall inhibition.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In deep PFC layers, β2 subunits occur on interneurons, layer VI pyramidal cells, and excitatory inputs to layer V pyramidal cells.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Layer V pyramidal neurons also contain postsynaptic α7 nAChRs.

    “In addition to presynaptic β2* nAChRs that can augment its activity, layer V pyramidal neurons also contain postsynaptic α7 nAChRs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Adolescent smoking is associated with working memory and attention disturbances and reduced PFC activation.

    “Several studies indicate that smoking during adolescence is associated with disturbances in working memory and attention as well as reduced PFC activation (Jacobsen et al. 2005, 2007; Musso et al. 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jacobsen et al. 2005, 2007

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

    • cites Musso et al. 2007 source

  • May combine two claims.

    Premisecitation

    nAChRs can alter pyramidal neuron activity by enhancing glutamatergic inputs or directly activating postsynaptic receptors.

    “nAChRs can alter pyramidal neuron activity by enhancing glutamatergic inputs or by activating postsynaptic receptors directly (Poorthuis et al. 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poorthuis et al. 2009 source

  • May combine two claims.

    Interpretationown data

    Similar mechanisms may operate across prefrontal cortex layers because non-fast-spiking cells in all layers express nAChRs.

    “Similar mechanisms may play a role across PFC layers because we find that non-fast-spiking cells in all layers express nAChRs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Fast-spiking cells in prefrontal cortex layers II-III contain α7 nAChRs, and about half of fast-spiking cells in layer V do as well.

    “Fast-spiking cells in PFC layers II–III contain α7 nAChRs, as do about half of the fast-spiking cells in layer V (Poorthuis et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poorthuis et al. 2012

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

  • May combine two claims.

    Interpretationcitation

    The correlation between smoking duration and reduced PFC activity suggests that nicotine's harmful effects progress and may persist into later life.

    “indicating a progression of deleterious effects of nicotine which may last into later life (Musso et al. 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Musso et al. 2007 source

  • May combine two claims.

    Premisecitation

    Regular-spiking and somatostatin-positive cells in prefrontal cortex layers II-III and V are positive for nAChRs, suggesting nAChRs modulate feedback inhibition among pyramidal neurons in these layers.

    “Regular-spiking and somatostatin-positive cells in PFC layers II–II and V are positive for nAChRs, suggesting that nAChRs play an important role in modulating feedback inhibition among pyramidal neurons in these layers (Poorthuis et al. 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Poorthuis et al. 2012

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

  • May combine two claims.

    Premisecitation

    Adolescent tobacco use is associated with later risk of mental and behavioral problems including major depressive disorder, agoraphobia, panic disorder, other substance addiction, antisocial personality disorder, and academic problems.

    “Several studies have shown that adolescent tobacco use is associated with later risk of developing mental and behavioral problems such as major depressive disorder, agoraphobia, panic disorder, addiction to other substances, antisocial personality disorder, or academic problems (Brown et al. 1996; Brook et al. 1998, 2002; Johnson et al. 2000; McGee et al. 2000; Ellickson et al. 2001).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Brown et al. 1996 source
    • cites Brook et al. 1998, 2002

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

    • cites Johnson et al. 2000

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

  • May combine two claims.

    Interpretationcitation

    The visuospatial attention effects of adolescent nicotine treatment suggest impaired attention and lack of impulse control.

    “This suggests impaired attention and lack of impulsive control, which is part of normal adolescent maturation (Counotte et al. 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Counotte et al. 2009 source

  • May combine two claims.

    Premisecitation

    mGlu2/3 receptors play an important role in drug dependence and in the negative affective state during withdrawal.

    “they play an important role in the development of drug dependence and the expression of the negative affective state observed during withdrawal (Kenny and Markou 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kenny and Markou 2004

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

  • May combine two claims.

    Premisecitation

    In reward-processing areas such as VTA and NAcc, lasting mGluR2 adaptations follow nicotine exposure and affect nicotine's rewarding properties.

    “Also in other brain areas involved in reward processing such as ventral tegmental area (VTA) and the nucleus accumbens (NAcc) lasting adaptations in mGluR2 function follow nicotine exposure and were found to affect rewarding properties of nicotine (Helton et al. 1997; Kenny et al. 2003; Kenny and Markou 2004; Liechti et al. 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Helton et al. 1997 source
    • cites Kenny et al. 2003

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

    • cites Kenny and Markou 2004

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

  • May combine two claims.

    Interpretationreasoning

    Lasting reduction of mGluR2 levels and function after adolescent nicotine exposure reduces inhibitory feedback on pyramidal cells and reduces mGluR2's regulatory role in short-term plasticity.

    “The lasting reduction of mGluR2 levels and function after adolescent nicotine exposure leads to reduced inhibitory feedback on pyramidal cells and reduces the regulatory role of this receptor in short-term plasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Adolescent but not adult nicotine treatment reduces accuracy in a visuospatial attentional task and increases premature and time-out responses.

    “Adolescent, but not adult, nicotine treatment reduces accuracy of correct stimulus detection in a visuospatial attentional task, with an increase in premature and time-out responding.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Counotte et al. 2009 source

  • May combine two claims.

    Premisecitation

    In rodents, adolescent nicotine treatment produces reduced DNA and altered protein/DNA ratio in cortical regions, indicating cell loss and altered cell size.

    “Also changes in macromolecular constituents indicative of cell loss (reduced DNA) and altered cell size (protein/DNA ratio) can be seen in cortical regions of rodents after adolescent nicotine treatment (Trauth et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Trauth et al. 2000 source

  • May combine two claims.

    Interpretationcitation

    mGluR2 signaling is a good candidate for shaping cognitive behavior, and its impairment leads to cognitive disturbances.

    “Thus, mGluR2 signaling seems to be a good candidate for shaping cognitive behavior and its impairment leads to disturbances in cognitive function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Adolescent smokers have attention deficits that worsen with more years of smoking.

    “In addition, adolescent smokers suffer from attention deficits, which aggravate with the years of smoking.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Musso et al. 2007 source

  • May combine two claims.

    Interpretationreasoning

    In prefrontal networks, nicotine modulates information processing at multiple levels by activating and desensitizing nicotinic receptors on different cell types, thereby affecting cognition.

    “In prefrontal networks nicotine modulates information processing on multiple levels by activating and desensitizing nicotine receptors on different cell types and in this way affects cognition.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Changes in inhibitory tone and excitatory transmission after adolescent nicotine exposure may have different short- and long-term effects on long-term plasticity.

    “Changes in inhibitory tonus and excitatory transmission following adolescent nicotine exposure may have different short- and long-term effects on long-term plasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Adolescent smoking increases the risk of developing psychiatric disorders and cognitive impairment later in life.

    “Studies in human subjects indicate that smoking during adolescence increases the risk of developing psychiatric disorders and cognitive impairment in later life.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Jacobsen et al. 2005, 2007

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

    • cites Musso et al. 2007 source
    • cites Brown et al. 1996 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Increased glutamatergic transmission in adult PFC caused by reduced mGluR2 function could impair plasticity types other than short-term depression, such as long-term plasticity.

    “A consequence of increased glutamatergic transmission in adult PFC caused by reduced mGluR2 function could be the impairment of other types of plasticity than STD, such as mechanisms of long-term plasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    mGluR2 levels on presynaptic glutamatergic terminals in PFC are increased, reducing glutamatergic synapse strength.

    “In addition, mGluR2 levels on presynaptic glutamatergic terminals in the PFC are increased, causing a reduction in glutamatergic synapse strength (Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    At this later stage, mGluR2 levels are significantly below baseline, altering mGluR2 signaling during short-term plasticity and impairing attention performance.

    “In contrast, at this stage, mGluR2 levels have reduced significantly below baseline levels, thereby altering mGluR2 signaling during short-term plasticity and hampering attention performance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The adolescent brain is in a vulnerable state of imbalance and is susceptible to psychoactive substances such as nicotine.

    “This places the adolescent brain in a vulnerable state of imbalance, susceptible to the influence of psychoactive substances such as nicotine.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The prefrontal cortex matures late and continues developing through adolescence.

  • May combine two claims.

    Interpretationreasoning

    In rodent brain, short-term adolescent but not adult nicotine exposure increases α4β2 nAChR expression in medial PFC, leading to increased nicotine-induced GABAergic synaptic transmission.

    “From studies in the rodent brain it is becoming clear that on the short-term, adolescent, but not adult, nicotine exposure increases the expression of nAChRs containing α4 and β2 subunits in the medial PFC, which leads to an increase in nicotine-induced GABAergic synaptic transmission.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Short-term depression shapes information transfer in synaptic networks and gives rise to sensory and behavioral phenomena.

    “In this manner it shapes the information transfer by synaptic networks and gives rise to sensory and behavioral phenomena (Zucker 1989).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zucker 1989

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

  • Classified as probably not a substantial claim.

    Premisecitation

    Presynaptic Ca2+ dynamics play a key role in short-term plasticity.

    “Because presynaptic Ca2+ dynamics play a key role in short-term plasticity (Zucker and Regehr 2002)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zucker and Regehr 2002 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In rat somatosensory cortex, synaptic depression of thalamic input contributes to rapid adaptation of sensory responses.

    “in the somatosensory cortex of rat, in vivo whole-cell recordings in cortical neurons during whisker deflection directly showed that synaptic depression of thalamic input to the cortex contributes to rapid adaptation of sensory responses (Chung et al. 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chung et al. 2002 source
57 of 57

  • The paper relies on this without support.

    Nicotine is psychoactive and addictive and acts directly on brain regions involved in emotional and cognitive processing.

    “Nicotine is also a psychoactive and addictive substance that directly acts on brain areas involved in emotional and cognitive processing.”

  • The paper relies on this without support.

    In the brain, nicotine binds to nicotinic acetylcholine receptors, which participate in cholinergic signaling in the prefrontal cortex.

    “Once in the brain, it binds to its target, the nicotinic acetylcholine receptors (nAChR), which take part in cholinergic signaling in the PFC.”

  • The paper relies on this without support.

    In deep PFC layers, β2 subunits occur on interneurons, layer VI pyramidal cells, and excitatory inputs to layer V pyramidal cells.

    “In the deep layers of the PFC, β2 subunits are expressed by both interneurons, as well as layer VI pyramidal neurons and excitatory inputs to layer V pyramidal neurons.”

  • The paper relies on this without support.

    The prefrontal cortex matures late and continues developing through adolescence.

    “The prefrontal cortex, the brain area responsible for executive functions and attention performance, is one of the last brain areas to mature and is still in the process of developing during adolescence.”

  • The paper relies on this without support.

    Long-lasting synaptic changes require intracellular signaling pathways and enzymes such as ERK and CREB.

    “Lasting synaptic adaptations involve activation of intracellular signaling pathway and such enzymes as extracellular regulated protein kinase (ERK) and cAMP response element binding protein (CREB).”
5 of 5

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?

  • Five weeks after nicotine exposure, LTP was enhanced in the medial prefrontal cortex in animals exposed to nicotine during adolescence, but not adulthood, indicating an inhibitory/excitatory switch produced by adolescent nicotine exposure.

    “Conversely, 5 wk after nicotine exposure, LTP was enhanced in the medial prefrontal cortex in animals exposed to nicotine during adolescence, but not adulthood, indicating an inhibitory/excitatory switch produced by adolescent nicotine exposure.”

    From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Goriounova and Mansvelder 2012

    The section “Lasting Synaptic Adaptations in the PFC That Affect Cognitive Performance in Later Life” (page unavailable) reports that mGluR2 levels are down-regulated five weeks after adolescent nicotine exposure, reducing inhibitory feedback in prefrontal synapses. It does not report enhanced LTP at that time or compare LTP after adolescent versus adult exposure. The proposed inhibitory-to-excitatory switch therefore goes beyond what this passage establishes. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Adolescent nicotine exposure produced a significant reduction in medial prefrontal cortex LTP 1-4 d after the last exposure.

    “Goriounova and Mansvelder (2012) found that adolescent nicotine exposure produced a significant reduction in medial prefrontal cortex LTP 1–4 d after the last exposure.”

    From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Goriounova and Mansvelder 2012

    The Concluding Remarks report reduced glutamatergic synapse strength in the medial prefrontal cortex after adolescent nicotine exposure, but do not report an LTP measurement. A search for LTP found a discussion of LTP induction in the hippocampus, not a significant reduction in medial prefrontal cortex LTP 1–4 days after exposure. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • In HC slices, blockade of the mGluR2 prevented the acute reduction in LTP found in adolescent nicotine exposed animals, whereas activation of the mGluR2 prevented the excessive LTP observed in adult rats previously exposed to nicotine during adolescence.

    “In HC slices, blockade of the mGluR2 prevented the acute reduction in LTP found in adolescent nicotine exposed animals, whereas activation of the mGluR2 prevented the excessive LTP observed in adult rats previously exposed to nicotine during adolescence (Goriounova and Mansvelder 2012).”

    From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Goriounova and Mansvelder 2012

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

    Experimental — accuracy not yet measured

  • Laboratory rodent studies provide strong evidence that isolated adolescent nicotine exposure produces long-lasting learning and cognitive deficits.

    “studies of laboratory rodents provide strong evidence that isolated nicotine exposure during adolescence produces long-lasting deficits in learning and cognitive processes.”

    From Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products (2017) · cites this paper as [289]

  • Adolescent nicotine exposure altered adult medial prefrontal cortical long-term potentiation of synaptic activity.

    “adolescent nicotine exposure altered adult medial prefrontal cortical long-term potentiation of synaptic activity.”

    From Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products (2017) · cites this paper as [289]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting estimates of adolescents who have tried smoking

    Minor

    The abstract says more than 70% of adolescents have smoked at least once, while the body says up to 70% have experimented with smoking. As stated, the estimates place the same proportion on opposite sides of 70%.

1 of 1

Cites

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2 of the 141 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Goriounova, N. A., & Mansvelder, H. D.
Affiliations
Amsterdam Neuroscience (NL)
ORCID
Venue
Cold Spring Harbor Perspectives in Medicine
Publisher
Cold Spring Harbor Laboratory
Published
2012-09-13
Volume
2
Issue
12
Pages
a012120-a012120
ISSN
2157-1422 (ISSN-L)
DOI
10.1101/cshperspect.a012120
PMC
PMC3543069
OpenAlex
W2100776577
Cited by
307
References
141
Citations by year
2026: 37 · 2025: 32 · 2024: 41 · 2023: 26 · 2022: 31 · 2021: 33 · 2020: 35 · 2019: 20 · 2018: 19 · 2017: 11 · 2016: 11 · 2015: 4 · 2014: 7
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • VU Research Portal (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Vrije Universiteit Amsterdam
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (917.76.360)
Topics
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
adolescent nicotine exposure, prefrontal cortex, adolescent smoking, brain maturation, synaptic plasticity, attention deficits, executive function, cognitive impairment, mental illness
MeSH terms
Adolescent, Animals, Brain Diseases, Cognition Disorders, Ganglionic Stimulants, Humans, Nerve Net, Neurons, Nicotine, Smoking, Synapses, Up-Regulation, Prefrontal Cortex, Rats, Executive Function

About these checks

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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