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Cited by 67Smoking Behavior and CessationNicotinic Acetylcholine Receptors StudyPrenatal Substance Exposure Effects

Nicotine addiction and psychiatric disorders

Open access
Kutlu, Munir Gunes, Parikh, Vinay, Gould, Thomas J.·2015·International Review of Neurobiology
DOI 10.1016/bs.irn.2015.08.004PMC PMC5755398
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Abstract

Even though smoking rates have long been on the decline, nicotine addiction still affects 20% of the US population today. Moreover, nicotine dependence shows high comorbidity with many mental illnesses including, but are not limited to, attention deficit hyperactivity disorder, anxiety disorders, and depression. The reason for the high rates of smoking in patients with mental illnesses may relate to attempts to self-medicate with nicotine. While nicotine may alleviate the symptoms of mental disorders, nicotine abstinence has been shown to worsen the symptoms of these disorders. In this chapter, we review the studies from animal and human research examining the bidirectional relationship between nicotine and attention deficit hyperactivity disorder, anxiety disorders, and depression as well as studies examining the roles of specific subunits of nicotinic acetylcholine receptors (nAChRs) in the interaction between nicotine and these mental illnesses. The results of these studies suggest that activation, desensitization, and upregulation of nAChRs modulate the effects of nicotine on mental illnesses.

AI snapshot

Written from the paper’s full text.

TL;DR

This chapter reviews human and animal evidence that nicotine dependence is bidirectionally linked with ADHD, anxiety disorders, and depression, with smoking rates elevated in these psychiatric populations and nicotine often used for self-medication. It concludes that acute nicotine may transiently alleviate symptoms, but withdrawal worsens them, and nAChR subtypes such as α4β2, β2-containing, and α7 modulate these effects.

Key findings

  • Smoking is elevated in psychiatric populations: nicotine addiction affects 20% of the US population, while 41% of individuals reporting past-month mental illness smoke; smoking is 45.3% in anxiety disorders versus 22.5% in the nonclinical population, and nicotine dependence is 22% in anxiety disorders versus 11.1% in the nondependent population.
  • In ADHD, 42% of males and 38% of females with ADHD were smokers versus 28.1% and 23.5% without ADHD; the quit ratio was 29% versus 48.5%, and lifetime tobacco dependence was 40% versus 19%. Acute nicotine improved attention and behavioral inhibition in ADHD, but withdrawal worsened symptoms and predicted relapse.
  • In anxiety/PTSD, PTSD patients who never smoked showed higher β2 nAChR density in mesiotemporal cortex; acute nicotine enhances hippocampus-dependent fear conditioning and impairs extinction, withdrawal impairs fear learning, and β2-containing nAChRs are required for these effects.
  • In depression, nicotine dependence predicted a threefold risk of developing major depression, adolescent smoking was associated with a fourfold increase in later depressive symptoms, and heavy smokers had four times higher risk of depression; animal models show antidepressant-like effects of nicotine involving β2-containing and α7 nAChRs.

Methods

  • Narrative review of animal and human studies examining bidirectional relationships between nicotine and ADHD, anxiety disorders, and depression, as well as roles of specific nAChR subunits.
  • No primary data collection; synthesizes cited human epidemiological/clinical studies and rodent/mouse models, including fear conditioning, 5-choice serial reaction time task, forced swim test, knockout, and pharmacological studies.
  • Main analysis is qualitative synthesis; no meta-analysis or statistical pooling is reported.

Limitations

  • The paper states further work is needed to understand underlying mechanisms, including unresolved issues such as the neurobiological substrates and whether nicotine is sufficient to increase ADHD susceptibility; animal anxiety results are described as contradictory and varying by strain/species and task.
  • The paper notes difficulty determining causality in human developmental exposure, since mothers who smoke during pregnancy may be self-medicating ADHD or subclinical ADHD symptoms, and offspring ADHD could reflect inherited risk; laboratory animal models are proposed to address this.
  • Evident from the text: as a review chapter, it presents no new experimental data, and some cited findings are explicitly said to require further examination, such as the discrepancy between α7 agonist studies and α7 knockout studies on attention.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/bs.irn.2015.08.004

Cites

246 of 246 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 148 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Activation, desensitization, and upregulation of nicotinic acetylcholine receptors modulate the effects of nicotine on mental illnesses.

    “The results of these studies suggest that activation, desensitization, and upregulation of nAChRs modulate the effects of nicotine on mental illnesses.”
    Quote in the paperSubstantial claim
  • Interpretationcitation

    Smoking can worsen attention problems.

    “This study suggests that smoking can worsen attention problems.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Treur et al., in press

      Not checked in the free run.

  • Interpretationreasoning

    Smoking may be an attempt to self-medicate for symptoms of ADHD.

    “Therefore, smoking may be an attempt to self-medicate for symptoms of ADHD.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Nicotine abstinence has been shown to worsen the symptoms of mental disorders.

    “While nicotine may alleviate the symptoms of mental disorders, nicotine abstinence has been shown to worsen the symptoms of these disorders.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Both male and female smokers with ADHD had a greater level of nicotine dependence than smokers without ADHD.

    “Furthermore, another study found that both male and female smokers with ADHD had a greater level of nicotine dependence than smokers without ADHD (Wilens et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wilens et al., 2008 source

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  • Classified as probably not a substantial claim. 4

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    Premisecitation

    The rate of smoking in individuals who reported mental illness in the past month was 41%, about double the CDC rate for the general population.

    “In support, the rate of smoking in individuals that reported mental illness in the past month was 41% (Lasser et al., 2000). This is a doubling of what is reported by the CDC for the general population.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lasser et al., 2000 source

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  • May combine two claims.

    Interpretationreasoning

    Differences in nAChR function may contribute to increased vulnerability to nicotine addiction for individuals with ADHD, and genetics plays a role in this vulnerability.

    “These studies suggest that differences in nAChR function may contribute to increased vulnerability to nicotine addiction for individuals with ADHD and that genetics plays a role in this vulnerability.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The high rates of smoking in patients with mental illnesses may relate to attempts to self-medicate with nicotine.

    “The reason for the high rates of smoking in patients with mental illnesses may relate to attempts to self-medicate with nicotine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Forty-two percent of males with ADHD and 38% of females with ADHD were smokers, compared with 28.1% and 23.5% of males and females without ADHD.

    “Forty-two percent of males with ADHD were smokers and 38% of females with ADHD were smokers; this compares to 28.1% and 23.5% smokers for males and females without ADHD (Pomerleau, Downey, Stelson, & Pomerleau, 1995).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pomerleau, Downey, Stelson, & Pomerleau, 1995

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    Interpretationcitation

    A complex relationship exists between ADHD and smoking, with ADHD contributing to smoking and smoking also contributing to the development of attention deficits.

    “Evidence suggests a complex relationship exists between ADHD and smoking with ADHD contributing to smoking but smoking also contributing to the development of attention deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Initially nicotine may have positive effects on cognitive/attentional control and response inhibition, but with prolonged use the positive effects disappear and cognitive functions may worsen in ADHD.

    “Together, these studies suggest that initially nicotine may have positive effects on cognitive/attentional control and response inhibition but with prolonged used, the positive effects disappear and cognitive functions may worsen in ADHD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Cholinergic function is required for normal attentional processes, and modulation of cholinergic signaling alters attention.

    “Together, these results provide support for the hypothesis that cholinergic function is required for normal attentional processes and that modulation of cholinergic signaling alters attention.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Prenatal and adolescent nicotine exposure contribute to the development of ADHD.

    “Collectively, these studies suggest that prenatal and adolescent nicotine exposure contribute to the development of ADHD, and thus, limiting nicotine exposure during development is of critical importance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Nicotine dependence may increase vulnerability to anxiety disorders, while smoking may alleviate symptoms associated with anxiety disorders, which in turn increases nicotine dependence among patients with anxiety disorders.

    “Therefore, it is possible that while nicotine dependence increases one’s vulnerability to anxiety disorders, smoking may serve as a mean to alleviate symptoms associated with anxiety disorders, which, in turn, increases nicotine dependence among patients with anxiety disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    During chronic nicotine administration, hippocampal nAChRs desensitize and upregulate, and the resulting hypersensitive cholinergic system may be responsible for the effects of nicotine withdrawal on hippocampus-dependent learning.

    “There is also evidence suggesting that during chronic nicotine administration, hippocampal nAChRs desensitize and upregulate and the resulting hypersensitive cholinergic system may be responsible for the effects of nicotine withdrawal on hippocampus-dependent learning (Dani & Heinemann, 1996; Gould et al., 2012; Marks, Grady, & Collins, 1993; Wilkinson & Gould, 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dani & Heinemann, 1996 source

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    • cites Gould et al., 2012 source

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    • cites Marks, Grady, & Collins, 1993

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    Premisecitation

    The presence of PTSD symptoms such as hyperarousal and emotional numbing is a predictor for nicotine dependence, and these symptoms are reduced by nicotine intake.

    “Furthermore, several studies have shown that the presence of PTSD symptoms, such as hyperarousal and emotional numbing, is a predictor for nicotine dependence and these symptoms are reduced by nicotine intake (Beckham et al., 2005; Feldner et al., 2007; Greenberg et al., 2012; Thorndike, Wernicke, Pearlman, & Haaga, 2006).”
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    • cites Feldner et al., 2007 source

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    • cites Greenberg et al., 2012 source

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    Premisecitation

    Acute nicotine enhances hippocampus-dependent contextual and trace fear conditioning, whereas it has no effect on hippocampus-independent cued fear conditioning.

    “For example, there is ample evidence suggesting that acute nicotine enhances hippocampus-dependent contextual (Davis, Porter, & Gould, 2006; Gould, 2003; Gould, Feiro, & Moore, 2004; Gould & Higgins, 2003; Gould & Wehner, 1999; Wehner et al., 2004) and trace (Davis & Gould, 2007; Gould et al., 2004) fear conditioning, whereas it has no effect on hippocampus-independent cued fear conditioning (e.g.”
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    • cites Davis, Porter, & Gould, 2006

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    • cites Gould, 2003

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    • cites Davis & Gould, 2007

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    Premisecitation

    Prior smoking is associated with increased susceptibility to develop PTSD in the event of a trauma and with increased risk of panic attacks and development of panic disorders.

    “Consistent with the high rates of nicotine dependence in patients with anxiety disorders, prior smoking has been found to be associated with increased susceptibility to develop PTSD in the event of a trauma (Koenen et al., 2005), an increased risk of panic attacks and development of panic disorders (Goodwin, Lewinsohn, & Seeley, 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Koenen et al., 2005 source

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    • cites Goodwin, Lewinsohn, & Seeley, 2005

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    Premisecitation

    PTSD patients showed lower rates of quitting, worse nicotine withdrawal symptoms, and shorter times to first smoking lapse than the non-PTSD population.

    “PTSD patients also showed lower rates of quitting (Hapke et al., 2005; Lasser et al., 2000), suffered from worse nicotine withdrawal symptoms (Dedert et al., 2011), and as a result showed shorter times to first smoking lapse (Beckham, Calhoun, Dennis, Wilson, & Dedert, 2012) than non-PTSD population.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hapke et al., 2005 source

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    • cites Dedert et al., 2011 source

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    Premisecitation

    Fear extinction is widely utilized as a translational animal model for exposure therapies used for anxiety disorders.

    “Fear extinction has been widely utilized as a translational animal model for the exposure therapies used for anxiety disorders (Briscione et al., 2014; Myers & Davis, 2006; Quirk & Mueller, 2007).”
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    • cites Briscione et al., 2014 source

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    • cites Myers & Davis, 2006

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    • cites Quirk & Mueller, 2007 source

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  • May combine two claims.

    Interpretationcitation

    Nicotine withdrawal and tolerance are dissociable processes: rapidly developing nAChR desensitization may be responsible for tolerance effects, whereas upregulation of nAChRs is necessary for withdrawal effects.

    “Therefore, this suggests that the rapidly developing nAChR desensitization may be responsible for the tolerance effects, whereas upregulation of nAChRs, which requires a longer period of time to develop, is necessary for the withdrawal effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gould, Wilkinson, Yildirim, Blendy, & Adoff, 2014

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  • May combine two claims.

    Premisecitation

    Acute nicotine administered during the extinction phase enhanced extinction and impaired renewal of cued fear memories.

    “Elias et al. (2010) found that acute nicotine enhanced extinction and impaired renewal of cued fear memories when administered during the extinction phase”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Elias et al. (2010) source

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    Premisecitation

    Nicotine administration during both training and extinction phases impaired extinction and enhanced renewal of cued fear.

    “whereas nicotine administration during both training and extinction phases impaired extinction and enhanced renewal of cued fear.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Elias et al. (2010) source

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  • May combine two claims.

    Interpretationnone given

    Acute nicotine enhances acquisition and impairs extinction of hippocampus-dependent fear memories.

    “numerous studies that have investigated the relationship between nicotine and fear learning suggest that acute nicotine enhances acquisition and impairs extinction of hippocampus-dependent fear memories.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Animal models of anxiety are widely utilized for neurobiological and pharmacological investigation of anxiety disorders.

    “Animal models of anxiety have been widely utilized for the neurobiological and pharmacological investigation of the anxiety disorders (Rodgers, 1997).”
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    • cites Rodgers, 1997 source

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  • May combine two claims.

    Premisecitation

    Prior chronic nicotine exposure impaired cued extinction but had no effect on contextual fear.

    “Tian and colleagues (2008) tested the effects of prior chronic nicotine exposure on subsequent extinction and showed that prior nicotine impaired cued extinction while having no effect of contextual fear.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tian and colleagues (2008)

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    Interpretationcitation

    Reinitiating smoking may enhance fear memories associated with new trauma and could prolong the course of PTSD.

    “Wilkinson and Gould’s (2013) results showing increased sensitivity to the effects of reintroduction of nicotine during nicotine withdrawal suggest that it may also enhance fear memories associated with new trauma and could prolong the course of the disorder.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wilkinson and Gould’s (2013)

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    Premisecitation

    Lower doses of acute nicotine at 0.01 and 0.1 mg/kg had anxiolytic effects, while higher doses at 0.5 and 1.0 mg/kg had anxiogenic effects in a social interaction test.

    “File, Kenny, and Ouagazzal (1998) found that lower doses of acute nicotine (0.01 and 0.1 mg/kg) also had anxiolytic effects, while higher doses (0.5 and 1.0 mg/kg) had anxiogenic effects in a social interaction test.”
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    • cites File, Kenny, and Ouagazzal (1998)

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    Premisecitation

    Rats tested 24 hours after the last nicotine injection showed increased anxiety during withdrawal, and this effect was reversed by dorsal hippocampal infusions of nicotine.

    “rats tested 24 h after the last nicotine injection showed increased anxiety during withdrawal and this effect was reversed by dorsal hippocampal infusions of nicotine (Irvine et al., 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Irvine et al., 2001 source

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  • May combine two claims.

    Interpretationcitation

    Activation of α7 nAChRs has an anxiogenic effect, while inactivation of these receptors via a partial α7 antagonist reverses the anxiogenic effects of nicotine withdrawal.

    “while activation of α7 nAChRs has an anxiogenic effect, inactivation of these receptors via using a partial antagonist α7 reverses the anxiogenic effects of nicotine withdrawal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Elimination of β2-containing nAChRs can prevent the anxiolytic effects of nicotine, while activation of these receptors can reverse the anxiogenic effects of nicotine withdrawal.

    “while elimination of β2-containing nAChRs can prevent the anxiolytic effects of nicotine, activation of these receptors can reverse the anxiogenic effects of nicotine withdrawal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nicotine injections 5 minutes before a social interaction test decreased social interaction, an anxiogenic effect, while injections 30 minutes before increased social interaction, an anxiolytic effect.

    “Irvine et al. (1999) found that nicotine injections 5 min before the behavioral test decreased social interaction, an anxiogenic effect, while injections 30 min before the task increased social interaction, an anxiolytic effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Irvine et al. (1999) source

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    Premisecitation

    Studies finding anxiogenic effects of nicotine used male hooded Lister rats, whereas studies showing anxiolytic effects used male Wistar rats or CD1 mice.

    “both Irvine et al. (1999, 2001) and Ouagazzal et al. (1999) studies, which found that nicotine has an anxiogenic effect, used male hooded Lister rats, whereas other studies showing anxiolytic effects of nicotine (Ericson et al., 2000; O’Neill & Brioni, 1994) used male Wistar rats or CD1 mice.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Irvine et al. (1999, 2001)

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    • cites Ouagazzal et al. (1999) source

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    • cites Ericson et al., 2000 source

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    Premisecitation

    The α4β2 nAChR agonist ABT-418 increased open arm time in the elevated plus maze, and both ABT-418 and the α4β2 partial agonist ABT-089 reversed the anxiogenic effects of nicotine withdrawal.

    “an α4β2 nAChR agonist, ABT-418, was found to increase open arm time in the EPM and both ABT-418 and an α4β2 nAChR partial agonist, ABT-089, reversed the anxiogenic effects of nicotine withdrawal (Brioni et al., 1994; Decker et al., 1994; Yohn, Turner, & Blendy, 2014).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brioni et al., 1994 source

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    • cites Decker et al., 1994 source

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    • cites Yohn, Turner, & Blendy, 2014

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  • May combine two claims.

    Interpretationcitation

    Human studies suggest that smoking may alleviate symptoms associated with anxiety disorders, while nicotine abstinence worsens those symptoms and results in higher rates of reinitiation of smoking.

    “While human studies suggest that smoking may alleviate the symptoms associated with anxiety disorders (Beckham et al., 2005; Feldner et al., 2007; Greenberg et al., 2012; Thorndike et al., 2006), nicotine abstinence worsens those symptoms (Dedert et al., 2011) and results in higher rates of reinitiation of smoking (Beckham et al., 2012; Hapke et al., 2005; Lasser et al., 2000).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Beckham et al., 2005 source

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    • cites Dedert et al., 2011 source

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    • cites Beckham et al., 2012 source

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    Premisecitation

    The risk of developing depression was four times higher in heavy smokers than nonsmokers, and increased time of smoking dependency was correlated with increased risk of depression.

    “the risk of developing depression was four times higher in heavy smokers than nonsmokers and increased time of smoking dependency was correlated with increased risk of depression (Klungsøyr, Nygård, Sørensen, & Sandanger, 2006)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Klungsøyr et al., 2006 source

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    Premisecitation

    α5 knockout animals showed no behavioral changes in the open field and light-dark box paradigms, while female knockout mice, but not male mice, showed reduced anxiety-like behavior in the elevated plus maze.

    “while α5 KO animals showed no behavioral changes in the OF and light–dark box paradigms, female KO mice, but not male mice, showed reduced anxiety-like behavior in the EPM.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gangitano et al. (2009) source

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    Premisecitation

    β4 knockout mice showed reduced anxiety in the elevated plus maze compared to wild-type littermates and reduced heart rate in this paradigm.

    “Salas, Pieri, Fung, Dani, and De Biasi (2003) showed that β4 KO mice showed reduced anxiety in the EPM compared to WT littermates as well as reduced heart rate in this paradigm.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Salas et al. (2003) source

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    Premisecitation

    Depression symptoms are important determinants of smoking initiation, maintenance, and cessation, whereas nicotine dependence is associated with vulnerability for depression.

    “Previous studies have shown that depression symptoms are important determinants of smoking initiation, maintenance, and cessation, whereas nicotine dependence is associated with vulnerability for depression (Breslau, Kilbey, & Andreski, 1991; Fergusson, Goodwin, & Horwood, 2003; Glassman et al., 1990; Hall, Muñoz, Reus, & Sees, 1993; Morrell & Cohen, 2006; Paperwalla, Levin, Weiner, & Saravay, 200”
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    • cites Breslau et al., 1991 source

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    • cites Fergusson et al., 2003 source

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    • cites Glassman et al., 1990 source

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  • May combine two claims.

    Interpretationcitation

    Animal studies using fear conditioning suggest that initial acute nicotine enhances hippocampus-dependent fear learning and impairs fear extinction, whereas acute nicotine during withdrawal further enhances hippocampus-dependent fear memories, which may prolong the disorder.

    “the animal studies using fear conditioning suggest that initial acute nicotine results in enhancement of hippocampus-dependent fear learning and impairment of fear extinction, whereas acute nicotine during nicotine withdrawal further enhances hippocampus-dependent fear memories, which may prolong the course of the disorder.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Smokers show higher rates of depression, and patients with major depression have higher levels of smoking than the nonclinical population.

    “Just as smokers show higher rates of depression, patients with major depression have been shown to have higher levels of smoking than the nonclinical population (Covey, Glassman, & Stetner, 1997, 1998; Fergusson et al., 2003).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Covey et al., 1997, 1998

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    • cites Fergusson et al., 2003 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    According to the self-medication hypothesis of nicotine dependence, nicotine reduces negative affect and works as an antidepressant.

    “According to the self-medication hypothesis of nicotine dependence (Carmody, 1992; Markou, Kosten, & Koob, 1998; Pomerleau & Pomerleau, 1985), this might be because nicotine reduces negative affect and works as an antidepressant.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Carmody, 1992 source

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    • cites Markou et al., 1998 source

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    • cites Pomerleau & Pomerleau, 1985 source

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    Premisecitation

    Varenicline increases nAChR activity and maintains it at a submaximal level, prevents binding of endogenous acetylcholine, and effectively desensitizes nAChRs.

    “varenicline increases nAChR activity and maintains it at a submaximal level, and therefore, it prevents binding of the endogenous acetylcholine and effectively desensitizes nAChRs (Mineur & Picciotto, 2010; Papke & Heinemann, 1994).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Mineur & Picciotto, 2010

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    • cites Papke & Heinemann, 1994

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    Premisecitation

    MLA, an α7-nAChR selective antagonist, reduced immobility in the forced swim test, while mecamylamine had antidepressant effects in the forced swim test for wild-type but not α7-nAChR knockout mice.

    “Andreasen, Olsen, et al. (2009) found that MLA (α7-nAChR selective antagonist) also reduced immobility in the FST, while another study found that mecamylamine had antidepressant effects in the FST for wild-type but not on α7-nAChR KO mice.”
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    • cites Andreasen, Olsen, et al. (2009)

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    Premisecitation

    Sazetidine-A, but not varenicline, decreased immobility in the forced swim test and tail-suspension test measures of depression.

    “Turner, Castellano, and Blendy (2010) reported that sazetidine-A, but not varenicline, decreased immobility in the FST and tail-suspension test measures of depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Turner et al. (2010) source

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    Premisecitation

    Nicotine had an antidepressant effect in the forced swim test, the chronic mild stress sucrose test, and learned helplessness.

    “nicotine had an antidepressant effect in the forced swim test (Andreasen & Redrobe, 2009; Suemaru et al., 2006; Tizabi, Getachew, Rezvani, Hauser, & Overstreet, 2009, Tizabi et al., 1999; Vázquez-Palacios, Bonilla-Jaime, & Velázquez-Moctezuma, 2005), the chronic mild stress sucrose test (Andreasen, Henningsen, Bate, Christiansen, & Wiborg, 2011), and learned helplessness (Semba, Mataki, Yamada, N”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Andreasen & Redrobe, 2009

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    • cites Andreasen et al., 2011 source

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    • cites Semba et al., 1998 source

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    Interpretationcitation

    Human studies suggest that initially smoking may alleviate symptoms of depression and works as self-medication, whereas smoking cessation results in exacerbation of depressive symptoms.

    “The human studies cited suggest that initially smoking may alleviate symptoms of depression and works as a mean to self-medicate, whereas smoking cessation results in the exacerbation of the depressive symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Symptoms of the disorders usually worsen during withdrawal, resulting in shorter periods of abstinence and eventually reinitiation of smoking.

    “This is because the symptoms of the disorders usually worsen during the period of withdrawal, which results in shorter period of abstinence and eventually reinitiation of smoking.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Parental lines of the 129SvJ-C57BL/6J F1 hybrid mice show differences in motor function, anxiety-related behavior, and sensorimotor responsivity, which may contribute to differential effects of partial nAChR agonists on depression-like behavior.

    “previous research showed that the parental lines of the 129SvJ-C57BL/6J F1 hybrid mice show differences in motor function, anxiety-related behavior, and sensorimotor responsivity, which may contribute to the differential effects of partial nAChR agonists on depression-like behavior (Tarantino, Gould, Druhan, & Bucan, 2000).”
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    • cites Tarantino et al., 2000 source

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44 of 44

  • The paper relies on this without support.

    Findings from animal models of nicotine exposure and nAChR function can be generalized to human psychiatric disorders such as ADHD and anxiety disorders.

    “Studies of laboratory animals can address these issues.”
    “Laboratory animal models provide a means to address these issues.”
1 of 1

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.

  • α4 knockout claim cites a point-mutant study

    Minor

    The text cites Labarca et al. (2001) in support of increased anxiety in α4 knockout mice, but its reference entry describes mice with a hypersensitive α4 point mutation, not an α4 knockout.

  • β2 knockout claim cites an α2 deletion study

    Minor

    The text cites Lotfipour et al. (2013) for a finding about mice lacking β2 receptors, but the cited reference describes deletion of the α2 subunit gene.

2 of 2

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Kutlu, M. G., Parikh, V., & Gould, T. J.
Affiliations
Temple University (US)
Corresponding author
Gould, Thomas J.
ORCID
Venue
International Review of Neurobiology
Publisher
Elsevier
Published
2015
Volume
124
Pages
171-208
ISSN
0074-7742 (ISSN-L)
DOI
10.1016/bs.irn.2015.08.004
PMC
PMC5755398
OpenAlex
W2417002138
Semantic Scholar
b757f3a90ef2d1bb4bd56d31fec894fe26504325
Cited by
65
References
241
Citations by year
2026: 10 · 2025: 8 · 2024: 8 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 3 · 2019: 9 · 2018: 2 · 2017: 4 · 2016: 9
FWCI
16.50
Type
book chapter
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • International review of neurobiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Drug Abuse (DA017949, R01DA017949)
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
nicotine dependence, psychiatric comorbidity, attention deficit hyperactivity disorder, anxiety disorders, depression, self-medication, nicotinic acetylcholine receptors, nAChR subunits, receptor desensitization, receptor up-regulation
MeSH terms
Mental Disorders, Humans, Nicotine, Receptors, Nicotinic, Tobacco Use Disorder

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 by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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