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Cited by 56Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationMemory and Neural Mechanisms

The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation

Open access
Gould, Thomas J., Portugal, George S., André, Jessica M., Tadman, Matthew P., Marks, Michael J., Kenney, Justin W., Yildirim, Emre, Adoff, Michael·2012·Neuropharmacology
DOI 10.1016/j.neuropharm.2012.01.003PMC PMC3278577
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Abstract

A predominant symptom of nicotine withdrawal is cognitive deficits, yet understanding of the neural basis for these deficits is limited. Withdrawal from chronic nicotine disrupts contextual learning in mice and this deficit is mediated by direct effects of nicotine in the hippocampus. Chronic nicotine treatment upregulates nicotinic acetylcholine receptors (nAChR); however, it is unknown whether upregulation is related to the observed withdawal-induced cognitive deficits. If a relationship between altered learning and nAChR levels exists, changes in nAChR levels after cessation of nicotine treatment should match the duration of learning deficits. To test this hypothesis, mice were chronically administered 6.3 mg/kg/day (freebase) nicotine for 12 days and trained in contextual fear conditioning on day 11 or between 1 to 16 days after withdrawal of treatment. Changes in [125I]-epibatidine binding at cytisine-sensitive and cytisine-resistant nAChRs and chronic nicotine-related changes in α4, α7, and β2 nAChR subunit mRNA expression were assessed. Chronic nicotine had no behavioral effect but withdrawal produced deficits in contextual fear conditioning that lasted 4 days. Nicotine withdrawal did not disrupt cued fear conditioning. Chronic nicotine upregulated hippocampal cytisine-sensitive nAChR binding; upregulation continued after cessation of nicotine administration and the duration of upregulation during withdrawal paralleled the duration of behavioral changes. Changes in binding in cortex and cerebellum did not match behavioral changes. No changes in α4, α7, and β2 subunit mRNA expression were seen with chronic nicotine. Thus, nicotine withdrawal-related deficits in contextual learning are time-limited changes that are associated with temporal changes in upregulation of high-affinity nAChR binding.

AI snapshot

Written from the paper’s full text.

TL;DR

Chronic nicotine treatment in mice produced time-limited withdrawal deficits in hippocampus-dependent contextual fear conditioning, lasting 4 days, while cued fear conditioning was unaffected. Hippocampal cytisine-sensitive high-affinity nAChR upregulation followed a similar time course, but the study was correlational and did not establish causation.

Key findings

  • Mice withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day freebase) showed disrupted contextual fear conditioning at 1, 2, 3, and 4 days post-withdrawal (p < 0.05), with no significant effect at days 5, 6, 7, 8, or 16; cued fear conditioning was not disrupted.
  • Chronic nicotine upregulated hippocampal cytisine-sensitive nAChR binding, and binding remained significantly elevated in withdrawn mice at 1, 2, 3, and 5 days after cessation; no significant hippocampal cytisine-resistant binding changes were observed.
  • Cortical and cerebellar binding changes did not match the behavioral time course: cortical cytisine-sensitive binding was increased only at day 3, cortical cytisine-resistant binding was elevated during chronic treatment and at day 3, and cerebellar cytisine-sensitive binding was increased during chronic treatment and at day 4.
  • No significant changes in hippocampal α4, α7, or β2 nAChR subunit mRNA expression were seen on the 12th day of chronic nicotine or after 24 hours of withdrawal.

Methods

  • Male C57BL/6J mice (8 and 12 weeks old, 20–28 g; n = 5–13 per group) received saline or nicotine bitartrate via subcutaneous mini-osmotic pumps at 6.3 mg/kg/day freebase for 12 days; pumps were removed to initiate withdrawal.
  • Contextual and cued fear conditioning were tested after chronic treatment or at withdrawal time points; separate mice were used for [125I]-epibatidine binding in cortex, hippocampus, and cerebellum, and for RT-qPCR of hippocampal α4, α7, and β2 nAChR subunit mRNA.
  • Data were analyzed with two-way ANOVAs and planned independent-samples t-tests with Bonferroni corrections, with significance at p ≤ 0.05.

Limitations

  • The paper states that the results show a correlational relationship and have not demonstrated causation; further in vitro and in vivo studies are needed.
  • The paper notes that learning deficits dissipated by day 5 while hippocampal binding was still elevated at day 5, suggesting either a threshold of upregulation or other contributing factors.
  • Evident from the text: only male mice were studied, α7 binding was not examined, mRNA was assessed only in hippocampus at the 12-day chronic treatment and 24-hour withdrawal time points, and the study did not use causal manipulations of nAChR upregulation.

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

Integrity signals

Registry

Crossref · 10.1016/j.neuropharm.2012.01.003

Cites

78 of 78 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

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  • Findingown data

    Chronic nicotine upregulates cytisine-sensitive nAChR binding in the hippocampus.

    “Chronic nicotine upregulated hippocampal cytisine-sensitive nAChR binding; upregulation continued after cessation of nicotine administration and the duration of upregulation during withdrawal paralleled the duration of behavioral changes.”
    • Also stated in: § 3.2 Nicotinic acetylcholine receptor binding · plain
      “Post hoc tests revealed that cytisine-sensitive nAChR binding in the hippocampus was significantly greater in mice treated with chronic nicotine and in mice withdrawn from chronic nicotine for 1, 2, 3, or 5 days (p < 0.05; Figure 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    Changes in nAChR binding in cortex and cerebellum did not match the behavioral changes.

    “Changes in binding in cortex and cerebellum did not match behavioral changes.”
    • Also stated in: § 3.2 Nicotinic acetylcholine receptor binding · plain
      “Changes in nAChR binding in the cortex and cerebellum were not consistent with the effects of nicotine withdrawal on contextual fear conditioning.”
    Quote in the paperSubstantial claim
  • Findingown data

    Cortex cytisine-sensitive nAChR binding was significantly increased only 3 days after withdrawal.

    “Planned Bonferroni comparisons revealed that cytisine-sensitive nAChR binding in the cortex was significantly increased only 3 days after withdrawal from chronic nicotine, and cytisine-resistant nAChR binding was elevated in mice treated with chronic nicotine and in mice withdrawn from chronic nicotine for 3 days (p < 0.05).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Nicotine withdrawal does not disrupt cued fear conditioning.

    “Nicotine withdrawal did not disrupt cued fear conditioning.”
    • Also stated in: § 3.1 Behavioral results · plain
      “There was no significant effect of nicotine withdrawal on baseline freezing, generalized freezing, or freezing to the cue (data for cued shown in Figure 1b).”
    Quote in the paperSubstantial claim
  • Findingown data

    Cerebellum cytisine-sensitive nAChR binding was significantly increased in chronic nicotine and 4 days after withdrawal.

    “Subsequent Bonferroni post-hoc tests revealed that cytisine-sensitive nAChR binding was significantly increased in mice treated with chronic nicotine and in mice withdrawn from chronic nicotine for 4 days relative to saline treated mice (p < 0.05).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingown data

    In cortex, cytisine-sensitive nAChR binding showed a significant main effect of treatment but no significant time or interaction effects.

    “Cytisine-sensitive nAChR binding in the cortex was examined with a 2 × 7 (treatment × time) ANOVA (see Table 2 for group means and standard error). A significant main effect for treatment [F(1, 98) = 10.18, p < 0.05] was observed, whereas the main effect of time and the interaction between treatment and time were not significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No effects of chronic nicotine or nicotine withdrawal were observed on baseline freezing or immediate freezing.

    “Furthermore, no effects of chronic nicotine or nicotine withdrawal were observed in baseline freezing or immediate freezing for all groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cortex, cytisine-resistant nAChR binding showed a significant main effect of treatment but no significant time or interaction effects.

    “For cytisine-resistant nAChR binding in the cortex, a 2 × 7 (treatment × time) ANOVA revealed a significant main effect for treatment [F(1, 98) = 21.68, p < 0.05], but the main effect of time and the interaction between treatment and time were not significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cerebellum, cytisine-sensitive nAChR binding showed significant main effects of treatment and time and a significant interaction.

    “In the cerebellum, cytisine-sensitive nAChR binding was with a 2 × 7 (treatment × time) ANOVA (see Table 2 for group means and standard error). A significant main effect for treatment [F(1, 98) = 32.59, p < 0.05], time [F(6, 98) = 6.12, p < 0.05], and a significant interaction between treatment and time [F(13, 98) = 2.31, p < 0.05] were observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In this study, chronic nicotine increased cytisine-sensitive binding in the cerebellum and hippocampus and cytisine-resistant binding in the cortex.

    “In the present study, chronic treatment with nicotine increased cytisine-sensitive binding in the cerebellum and hippocampus and cytisine-resistant binding in the cortex”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Learning deficits disappeared by day 5, but hippocampal binding was still elevated at day 5.

    “learning deficits dissipated by day 5 but hippocampus binding was elevated at day 5”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The duration of elevated cytisine-sensitive binding in the hippocampus closely matched the duration of nicotine withdrawal-associated deficits in contextual learning; hippocampal nAChR upregulation and hippocampus-dependent withdrawal learning deficits shared a common time course.

    “The duration of increased cytisine-sensitive binding in the hippocampus was highly similar to the duration of nicotine withdrawal-associated deficits in contextual learning.”
    • Also stated in: § 4. Discussion · plain
      “Upregulation of hippocampal nAChRs and withdrawal deficits in hippocampus-dependent learning shared a common time course.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the cerebellum, cytisine-sensitive binding returned to baseline immediately, with significantly more binding only on the fourth day after withdrawal.

    “In cerebellum, cytisine-sensitive binding returned to baseline immediately with only significantly more binding seen on the 4th day after withdrawal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No change in cytisine-resistant binding occurred in the hippocampus, and this binding was lower than cytisine-sensitive binding.

    “No change in cytisine-resistant binding, which was at a lower level than cytisine-sensitive binding, was seen in the hippocampus.”
    Quote in the paperNot a substantial claim

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    Findingown data

    In the cortex, cytisine-resistant binding returned to baseline immediately, with significantly more binding only on the fourth day after withdrawal.

    “In cortex, cytisine-resistant binding returned to baseline immediately, with only significantly more binding seen on the 4th day after withdrawal”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In mice, α4β2* nAChR binding sites increase during chronic nicotine treatment and return to control levels after cessation.

    “Similarly, a study in mice indicated that α4β2* nAChRs binding sites increased during chronic nicotine treatment and returned to control levels following cessation of treatment; these changes were related to the development and loss of tolerance (Marks et al., 1985).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Different brain regions and nAChR subtypes have different upregulation parameters.

    “While this prediction is straightforward, testing it has been confounded by the observation that different brain regions and nAChR subtypes have different upregulation parameters (Collins et al., 1989; Mao et al., 2008; Perry et al., 2007) and a lack of understanding of which brain regions are critically involved in specific withdrawal symptoms.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Collins et al., 1989 source

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    • cites Mao et al., 2008 source

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    Premisecitation

    These α4β2* binding changes are related to the development and loss of tolerance.

    “Similarly, a study in mice indicated that α4β2* nAChRs binding sites increased during chronic nicotine treatment and returned to control levels following cessation of treatment; these changes were related to the development and loss of tolerance (Marks et al., 1985).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Marks et al., 1985 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Elevated nAChR levels in abstinent smokers correlate with urge to smoke.

    “Abstinent smokers compared to nonsmokers had higher levels of β2* nAChRs, which returned to baseline between 3-12 weeks, and elevated nAChR levels correlated with urge to smoke (Cosgrove et al., 2009; Mamede et al., 2007; Staley et al., 2006).”
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    Premisecitation

    Abstinent smokers have higher β2* nAChR levels than nonsmokers, and these levels return to baseline within 3-12 weeks.

    “Abstinent smokers compared to nonsmokers had higher levels of β2* nAChRs, which returned to baseline between 3-12 weeks, and elevated nAChR levels correlated with urge to smoke (Cosgrove et al., 2009; Mamede et al., 2007; Staley et al., 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cosgrove et al., 2009 source

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    • cites Mamede et al., 2007 source

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    • cites Staley et al., 2006 source

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

    Study design and conductnone given

    All primers were tested for efficiency (100 ± 10%) and specificity before use.

    “All primers (see Table 1) were tested for efficiency (100 ± 10%) prior to use and specificity was examined using melt curves and running RT-qPCR products on an ethidium bromide stained agarose gel visualized via UV fluorescence.”
    Quote in the paperNot a substantial claim

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    Study design and conductnone given

    The first and second sets of mice were tested by independent investigators blind to experimental conditions.

    “The first set of mice and the second set were tested by independent investigators that were blind to experimental conditions.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The hippocampus is necessary and sufficient for nicotine withdrawal-related disruption of contextual fear conditioning.

    “These experiments demonstrate that the hippocampus is necessary and sufficient for nicotine withdrawal-related disruption of contextual fear conditioning.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Davis and Gould, 2009 source

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    Premisecitation

    Contextual fear conditioning requires the hippocampus, whereas cued fear conditioning does not.

    “In addition, the finding that withdrawal disrupted contextual but not cued fear conditioning adds to a growing literature that, at least in the mouse model, nicotine withdrawal disrupts hippocampus-dependent learning but not hippocampus-independent learning as contextual fear conditioning requires the hippocampus whereas cued fear conditioning does not (Fanselow et al., 1994; Logue et al., 1997;”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Study design and conductcitation

    mRNA expression levels were normalized by the geometric mean of GAPDH and HPRT.

    “The mRNA expression levels for each gene of interest were normalized by the geometric mean of two housekeeping genes, GAPDH and HPRT (Vandesompele et al., 2002), and relative expression was calculated with qbasePLUS software via the Ct method (Hellemans et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vandesompele et al., 2002 source

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    Premisecitation

    Withdrawal deficits in learning are mediated by β2* nAChRs but not α7 nAChRs.

    “These withdrawal deficits in learning are mediated by nicotinic acetylcholinergic receptors (nAChRs) containing the β2 subunits (β2* nAChR) but not by those containing the α7 subunit (α7 nAChR) (Davis and Gould, 2009; Portugal et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Davis and Gould, 2009 source

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    Premisecitation

    Previous work demonstrated that nicotine withdrawal disrupts acquisition but not recall of contextual fear conditioning.

    “Previous work demonstrated that nicotine withdrawal disrupts the acquisition but not the recall of contextual fear conditioning (Portugal and Gould, 2009) and therefore withdrawal time points are discussed in relationship to training.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Portugal and Gould, 2009

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    Premisecitation

    The C57BL/6J mouse strain performs well in fear conditioning and is sensitive to nicotine effects on learning.

    “This strain was chosen because it performs well in fear conditioning (Owen et al., 1997) and is sensitive to the effects of nicotine on learning (Kenney and Gould, 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Owen et al., 1997 source

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    • cites Kenney and Gould, 2008 source

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    Interpretationreasoning

    Nicotine withdrawal disrupts hippocampus-dependent learning but not hippocampus-independent learning.

    “In addition, the finding that withdrawal disrupted contextual but not cued fear conditioning adds to a growing literature that, at least in the mouse model, nicotine withdrawal disrupts hippocampus-dependent learning but not hippocampus-independent learning as contextual fear conditioning requires the hippocampus whereas cued fear conditioning does not (Fanselow et al., 1994; Logue et al., 1997;”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fanselow et al., 1994 source

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    • cites Logue et al., 1997 source

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    Premisecitation

    The 6.3 mg/kg/day nicotine dose produces plasma nicotine levels of approximately 13.00 ng/ml in mice, within the range seen in smokers.

    “The dose of nicotine was chosen based on our prior research demonstrating that it produced withdrawal deficits in contextual fear conditioning (André et al., 2008; Davis and Gould, 2007b) with plasma nicotine levels of approximately 13.00 ng/ml (Davis et al., 2005), which is within the range seen in smokers (Henningfield and Keenan, 1993).”
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    Study design and conductnone given

    Inter-rater reliability was established at >95% before the study.

    “Prior to the study, inter-rater reliability was established at >95%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Contextual fear conditioning depends on the hippocampus, while cued fear conditioning does not.

    “fear conditioning requires the hippocampus whereas cued fear conditioning does not (Fanselow et al., 1994; Logue et al., 1997; Phillips and Ledoux, 1992).”
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    • cites Fanselow et al., 1994 source

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    • cites Logue et al., 1997 source

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    • cites Phillips and Ledoux, 1992 source

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    Premisecitation

    The model is extrapolated from an earlier model by Dani and Heinemann (1996) in which, during low nicotine levels, upregulated nAChRs would be excessively responsive to ACh.

    “This model is extrapolated from an earlier model proposed by Dani and Heinemann (1996) in which during periods of low nicotine levels, upregulated nAChRs would be excessively responsive to ACh.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dani and Heinemann (1996) source

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    Premisecitation

    Chronic nicotine treatment causes upregulation of β2* nAChRs and also desensitization of nAChRs.

    “Chronic nicotine treatment results in an upregulation of β2* nAChRs (Marks et al., 1983; Schwartz and Kellar, 1983) but also a desensitization of nAChRs (Gentry and Lukas, 2002).”
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    • cites Marks et al., 1983 source

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    • cites Schwartz and Kellar, 1983 source

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    • cites Gentry and Lukas, 2002 source

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    Premisecitation

    Withdrawal-related learning deficits are specific to the hippocampus, as demonstrated for trace conditioning and spatial object recognition.

    “This hippocampal specificity for learning-related withdrawal deficits has been shown for other learning tasks such as trace conditioning and spatial object recognition (Kenney et al., 2011; Raybuck and Gould, 2009)”
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    • cites Kenney et al., 2011 source

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    • cites Raybuck and Gould, 2009

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    Premisecitation

    Non-α7 nAChRs remain upregulated longer than α7 nAChRs, which return to baseline almost immediately after nicotine cessation.

    “Non-α7 nAChRs show a longer lasting upregulation than α7 nAChRs, which return to baseline almost immediately after cessation of nicotine treatment (Marks et al., 1985).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Marks et al., 1985 source

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    Interpretationreasoning

    During nicotine withdrawal, desensitized nAChRs may return to a functional state while upregulation persists.

    “When nicotine is no longer present for an extended period of time (i.e, nicotine withdrawal), the desensitized nAChRs may return to a functional state while upregulation persists.”
    Quote in the paperSubstantial claim

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    Interpretationown data

    Either a threshold level of upregulation is needed before deficits appear, or other factors contribute to the deficits.

    “suggesting that either a level of upregulation that must occur before deficits are seen or other factors contribute to the deficits.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Non-α7 nAChRs, measured by high-affinity epibatidine binding, can be divided by their sensitivity to cytisine binding.

    “The non-α7 nAChRs, which are measured by high affinity epibatidine binding, can be further subdivided by sensitivity to cytisine binding.”
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    • cites Marks et al., 2006 source

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    Premisecitation

    Cytisine-sensitive binding corresponds to α4β2* nAChRs, while cytisine-resistant binding corresponds to α3β2*, α3β4*, and α6β2* nAChRs.

    “Cytisine-sensitive binding is associated with α4β2* nAChRs whereas cytisine-resistant binding is associated with α3β2*, α3β4*, and α6β2* nAChRs (Marks et al., 2006).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The nAChR antagonist property of bupropion could dampen nAChR response during withdrawal, alleviating withdrawal symptoms if they are due to a hyper-sensitive nACh system.

    “The nAChR antagonist property of bupropion could dampen nAChR response during withdrawal alleviating withdrawal symptoms, if the symptoms are due to a hyper-sensitive nACh system.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    If nicotine withdrawal deficits in learning and cognition are due to a hyper-sensitive nAChR system from functional upregulation, then drugs that ameliorate withdrawal symptoms should desensitize or dampen nAChR signaling.

    “If nicotine withdrawal deficits in learning and cognition are due to a hyper-sensitive nAChR system that results from functional upregulation, then drugs that ameliorate withdrawal symptoms should desensitize or dampen nAChR signaling.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The current results show a correlational relationship but have not demonstrated causation.

    “the current results show a correlational relationship but have not demonstrated causation.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Not all withdrawal symptoms are mediated by β2* nAChRs; β4*, α5*, and α7 nAChRs, but not β2* nAChRs, contribute to somatic withdrawal symptoms.

    “not all withdrawal symptoms are mediated by β2* nAChRs; for example, β4*, α5*, and α7 nAChRs, but not β2* nAChRs, contribute to somatic withdrawal symptoms (Jackson et al., 2008; Salas et al., 2007; Salas et al., 2004).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Jackson et al., 2008 source

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    • cites Salas et al., 2007 source

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    • cites Salas et al., 2004 source

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    Premisecitation

    Bupropion is a noradrenergic reuptake inhibitor and also a noncompetitive nAChR antagonist.

    “bupropion is a noradrenergic reuptake inhibitor but also a noncompetitive nAChR antagonist (Slemmer et al., 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Slemmer et al., 2000 source

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

    Interpretationreasoning

    Varenicline is a partial agonist and could reduce withdrawal deficits by occupying nAChRs.

    “Similarly, varenicline is a partial agonist and thus could ameliorate the withdrawal deficits by occupying nAChRs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This could produce a hyper-sensitive nACh system, which could cause cognitive deficits.

    “This could result in a hyper-sensitive nACh system, which could produce cognitive deficits.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Studies of abstinent smokers show a relationship between β2* nAChR concentration and cravings to smoke to reduce withdrawal symptoms.

    “results from studies of abstinent smokers showing a relationship between β2* nAChR concentration and cravings to smoke to reduce withdrawal symptoms (Staley et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Staley et al., 2006 source

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    Premisecitation

    Papke and colleagues (2011) showed that varenicline provided weak tonic activation of the nACh system but also decreased the effects of full agonists.

    “Papke and colleagues (2011) provide support for this position by demonstrating that while varenicline provided weak tonic activation of the nACh system, it also decreased the effects of full agonists.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Papke and colleagues (2011)

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Nicotine could reduce deficits by desensitizing nAChRs, bringing the system back toward baseline.

    “Nicotine could ameliorate deficits through desensitizing nAChRs, bringing the system back towards baseline.”
    Quote in the paperSubstantial claim
45 of 45

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?

  • The increased pool of nAChRs from chronic nicotine exposure may drive symptoms of nicotine withdrawal.

    “The increased pool of nAChRs arising from chronic nicotine exposure may drive symptoms associated with the nicotine withdrawal syndrome (Turner et al. 2011; Gould et al. 2012)”

    From Nicotine Withdrawal (2015) · cites this paper as Gould et al. 2012

    The Discussion (section 4; page not supplied) suggests that nAChR upregulation may contribute to nicotine withdrawal-related learning deficits. The claim broadens this possible mechanism to withdrawal symptoms generally, whereas the paper says different symptoms involve different receptors and that its results do not demonstrate causation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In rodents, nAChR upregulation in dorsal hippocampus is associated with withdrawal-related deficits in hippocampal learning.

    “Similarly, in rodents, nAChR upregulation in the dorsal hippocampus was associated with withdrawal-related deficits in hippocampal learning (Gould et al. 2012; Portugal et al. 2012).”

    From Nicotine Withdrawal (2015) · cites this paper as Gould et al. 2012

    The Results (§3.2) report hippocampal nAChR upregulation in mice with a time course consistent with withdrawal-related deficits in contextual learning; the Discussion (§4) describes the relationship as correlational. Our copy does not localize the measured upregulation specifically to the dorsal hippocampus, so that anatomical detail is unsupported. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Chronic nicotine treatment upregulates various nAChRs in the hippocampus, and the duration of β2 subunit upregulation most closely corresponds to the total duration of memory-associated withdrawal symptoms.

    “Furthermore, chronic nicotine treatment upregulated a variety of nAChRs in the hippocampus, and the duration of β2 subunit upregulation relative to other nAChR subunits most closely corresponded to the total duration of memory-associated withdrawal symptoms (Gould et al. 2012).”

    From Nicotine Withdrawal (2015) · cites this paper as Gould et al. 2012

    Results §3.2 (page unavailable) reports increased hippocampal cytisine-sensitive binding, associated with α4β2* receptors, on a time course similar to the contextual-learning withdrawal deficit. It found no increase in hippocampal cytisine-resistant binding; Results §3.3 found no increase in β2 subunit mRNA. The paper therefore supports a relationship involving β2-containing receptors, not the claim that various hippocampal receptor types were upregulated or that β2 subunit upregulation was compared with other subunits. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Nicotine withdrawal produces impairments in both contextual learning and attention-based models.

    “Conversely, nicotine withdrawal produces impairments in both contextual learning and attention-based models (Semenova et al. 2007; Gould et al. 2012; Portugal et al. 2012; Poole et al. 2014; Yildirim et al. 2015).”

    From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Gould et al. 2012

    The Discussion reports that nicotine withdrawal disrupted contextual fear conditioning in mice for four days. The paper does not report an impairment in attention-based models, so it supports only the contextual-learning part of the claim. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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).”

    From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Gould et al., 2012

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(1, 150) = 13.56reported p < .05 · recomputed p < .001

    “F(1, 150) = 13.56, p < .05”

  • ConsistentF(8, 150) = 2.79reported p < .05 · recomputed p = .007

    “F(8, 150) = 2.79, p < .05”

  • ConsistentF(17, 150) = 3.3reported p < .05 · recomputed p < .001

    “F(17, 150) = 3.30, p < .05”

  • ConsistentF(1, 98) = 28.53reported p < .05 · recomputed p < .001

    “F(1, 98) = 28.53, p < .05”

  • ConsistentF(6, 98) = 3.24reported p < .05 · recomputed p = .006

    “F(6, 98) = 3.24, p < .05”

  • ConsistentF(13, 98) = 3.3reported p < .05 · recomputed p < .001

    “F(13, 98) = 3.30, p < .05”

  • ConsistentF(1, 98) = 43.67reported p < .05 · recomputed p < .001

    “F(1, 98) = 43.67, p < .05”

  • ConsistentF(6, 98) = 3.05reported p < .05 · recomputed p = .009

    “F(6, 98) = 3.05, p < .05”

  • ConsistentF(1, 98) = 10.18reported p < .05 · recomputed p = .002

    “F(1, 98) = 10.18, p < .05”

  • ConsistentF(1, 98) = 21.68reported p < .05 · recomputed p < .001

    “F(1, 98) = 21.68, p < .05”

  • ConsistentF(1, 98) = 32.59reported p < .05 · recomputed p < .001

    “F(1, 98) = 32.59, p < .05”

  • ConsistentF(6, 98) = 6.12reported p < .05 · recomputed p < .001

    “F(6, 98) = 6.12, p < .05”

  • ConsistentF(13, 98) = 2.31reported p < .05 · recomputed p = .010

    “F(13, 98) = 2.31, p < .05”

13 of 13

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.

  • Incorrect interaction degrees of freedom for cerebellar binding

    Minor

    The reported cerebellar treatment-by-time interaction has 13 numerator degrees of freedom, whereas the stated 2 × 7 design gives 6.

  • Stated infusion rate is incompatible with pump volume

    Minor

    At the stated rate of 0.25 liters per hour, a pump containing only 100 μl would empty almost immediately, rather than administer treatment over the stated 12 days.

  • Incorrect interaction degrees of freedom for the behavioral 2 × 7 analysis

    Minor

    A treatment-by-time interaction in a 2 × 7 ANOVA has 6 numerator degrees of freedom, not 13.

  • Incorrect interaction degrees of freedom for the 2 × 9 analysis

    Minor

    A treatment-by-time interaction in a 2 × 9 ANOVA has (2−1) × (9−1) = 8 numerator degrees of freedom, not 17.

  • Conflicting days for increased cortical cytisine-resistant binding

    Minor

    The results report increased cortical cytisine-resistant binding three days after withdrawal, while the discussion places the increase on day four.

5 of 5

Cites

Flagged first, then by citations

3 of the 81 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Gould, T. J., Portugal, G. S., André, J. M., Tadman, M. P., Marks, M. J., Kenney, J. W., Yildirim, E., & Adoff, M.
Affiliations
  • Temple University (US)
  • University of Colorado Boulder (US)
Corresponding author
Gould, Thomas J.
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2012-04
Volume
62
Issue
5-6
Pages
2118-2125
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2012.01.003
PMC
PMC3278577
OpenAlex
W2015572742
Semantic Scholar
31a9c0bbbbd1b86eedeadb3f856f79064149993b
Cited by
56
References
81
Citations by year
2024: 2 · 2023: 5 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 6 · 2015: 5 · 2014: 13 · 2013: 7 · 2012: 2
FWCI
3.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
Funders
National Institute on Drug Abuse (CA143187, DA024787, DA003194, DA01749, DA07237)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
nicotine withdrawal, contextual fear conditioning, hippocampus, nicotinic acetylcholine receptors, receptor up-regulation, epibatidine binding, alpha4 subunit, alpha7 subunit, beta2 subunit, cued fear conditioning, cognitive impairment, chronic nicotine administration
MeSH terms
Animals, Conditioning, Psychological, Fear, Hippocampus, Nicotine, Receptors, Nicotinic, Substance Withdrawal Syndrome, Up-Regulation, Mice

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 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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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