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Cited by 28Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationNeuroscience and Neuropharmacology Research

Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors

Open access
Yohn, Nicole L., Turner, Jill R., Blendy, Julie A.·2014·The Journal of Pharmacology and Experimental Therapeutics
DOI 10.1124/jpet.113.211706PMC PMC3989801
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Abstract

Although nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist varenicline (Chantix; Pfizer, Groton, CT); however, treatment with this drug fails to alleviate anxiety in individuals during nicotine withdrawal. Therefore, it is hypothesized that success can be found by the repurposing of other nAChR partial agonists for cessation therapies that target anxiety. It is noteworthy that the selective partial agonists for α4β2, ABT-089 [2-methyl-3-[2(S)-pyrrolidinylmethoxy]pyridine], and α7, ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole] (AbbVie, North Chicago, IL), have not been evaluated as possible therapeutics for nicotine cessation. Therefore, we examined the effect of ABT-089 and ABT-107 on anxiety during withdrawal from nicotine in the novelty-induced hypophagia (NIH) paradigm. We found that short-term administration of ABT-089 and ABT-107 alleviate anxiety-like behavior during withdrawal from nicotine while long-term administration of ABT-089 but not ABT-107 reduces anxiety-like behavior during withdrawal. After behavioral testing, brains were harvested and β2-containing nAChRs were measured using [(3)H]epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed after nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotine-dependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids.

AI snapshot

Written from the paper’s full text.

TL;DR

Short-term ABT-089 and ABT-107 reduce anxiety-like behavior during 24-hour nicotine withdrawal in mice, but only long-term ABT-089 remains anxiolytic during extended withdrawal. ABT-089 alleviates withdrawal-induced anxiety without maintaining or producing upregulation of heteromeric nicotinic receptors.

Key findings

  • Short-term ABT-089 and ABT-107 reduced latency to consume in the novelty-induced hypophagia (NIH) test during 24-hour withdrawal from nicotine: ABT-107 significantly reduced latency versus saline controls (P < 0.01), and both ABT-089 and ABT-107 significantly reduced latency versus 24-hour nicotine withdrawal (P < 0.0001). Overall novel-day effects were significant [day F(1,35)=82.34, P<0.0001; treatment F(4,35)=9.736, P<0.0001; interaction F(4,35)=10.25, P<0.0001].
  • Long-term ABT-089, but not ABT-107, reduced anxiety-like behavior during nicotine withdrawal: planned comparison showed Nic/ABT-089 significantly reduced latency versus 7-day nicotine withdrawal (P < 0.05), whereas Nic/ABT-107 did not. The main effect of day was significant [F(1,24)=18.22, P=0.0003].
  • Long-term nicotine increased nAChRs in hippocampus, cortex, striatum, and thalamus (main effects: hippocampus F(4,27)=8.462, P=0.0001; cortex F(4,29)=15.91, P<0.0001; striatum F(4,29)=8.017, P=0.0002; thalamus F(4,28)=6.774, P=0.0006), but after 7 days of withdrawal receptors were no longer upregulated. ABT-089 and ABT-107 during withdrawal did not maintain upregulated nAChRs versus saline.
  • Long-term ABT-089 alone in nicotine-naive mice did not significantly upregulate nAChRs in hippocampus, cortex, striatum, or thalamus (P=0.6820, 0.6923, 0.3998, 0.0734, respectively). In nicotine-naive mice, long-term ABT-089 did not decrease anxiety-like behavior; 24-hour withdrawal from ABT-089 did not significantly increase latency versus saline, although the paper labels ABT-089 as anxiogenic in the abstract/title.

Methods

  • Male 129SvJ;C57Bl/6J F1 hybrid mice (6–12 weeks, 20–30 g) were used. Short-term drugs were injected intraperitoneally; long-term drugs were delivered subcutaneously via 14-day osmotic minipumps. Doses: short-term ABT-089 1.2 mg/kg and ABT-107 0.03 mg/kg; long-term nicotine 18 mg/kg/day, ABT-089 0.769 mg/kg/day, ABT-107 0.32 mg/kg/day.
  • Anxiety-like behavior was measured with the NIH paradigm: latency to consume peanut butter chips in home cage versus a novel environment after nicotine withdrawal and drug treatment. Short-term studies used 24-hour withdrawal; long-term studies used 7-day withdrawal and continued drug treatment.
  • Receptor binding used homogenate assays with 2 nM [3H]epibatidine in hippocampus, cortex, striatum, and thalamus; nonspecific binding was determined with 300 µM nicotine. Analyses used ANOVA, repeated-measures ANOVA, and Bonferroni post hoc tests in GraphPad Prism 5.0.

Limitations

  • The paper states that ABT-089’s anxiolytic effect is only evident when drug is on board, because latency to consume increased 7 days after withdrawal from ABT-089. It also states that the temporal specificity of discrete nAChR subtypes after withdrawal onset needs further study.
  • Evident from the text: all experiments used male mice of one hybrid strain, so sex and strain generalization are not established. Receptor binding was constrained by minimal tissue amount to four brain regions, and the study reports no human clinical outcomes.

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

Integrity signals

Registry

Crossref · 10.1124/jpet.113.211706

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Compared with nicotine withdrawal (7 days), ABT-107 did not significantly reduce latency to consume.

    “Planned comparison of Nic/ABT-089 and Nic/ABT-107 to other treatment groups revealed that compared with nicotine withdrawal (7 days), ABT-089 significantly reduced latency to consume (P , 0.05), whereas ABT-107 did not.”
    Quote in the paperSubstantial claim
  • Findingown data

    Long-term administration of ABT-089 during nicotine withdrawal reduced latency to consume compared with saline controls, although not significantly.

    “Data in Fig. 2B demonstrate that 14-day administration of ABT-089 and ABT-107 during nicotine withdrawal reduced latency to consume compared with saline controls, although not significantly [main effect of day, F(1,24) 5 18.22, P 5 0.0003].”
    Quote in the paperNot a substantial claim
  • Findingown data

    Animals undergoing spontaneous withdrawal from ABT-107 did not show reduced latency to consume in the novel environment compared with saline controls or nicotine withdrawal.

    “Animals in which minipumps were removed to induce spontaneous withdrawal from ABT-089 or ABT-107 did not show reduced latency to consume in the novel environment compared with saline controls or nicotine withdrawal.”
    Quote in the paperNot a substantial claim
  • Findingown data

    ABT-107 administration during withdrawal from nicotine does not maintain upregulated nAChRs compared with saline control animals.

    “ABT-089 (Nic/ABT-089) and ABT-107 (Nic/ ABT-107) administration during withdrawal from nicotine does not maintain upregulated nAChRs compared with saline control animals.”
    Quote in the paperSubstantial claim
  • Findingown data

    Mice experiencing 24-hour withdrawal from nicotine had significantly greater latency to consume compared with saline-treated controls.

    “Bonferonni post hoc analysis indicated that nicotine-treated mice had significantly lower latency to consume (P , 0.05), whereas mice experiencing 24-hour withdrawal from nicotine had significantly greater latency to consume (P , 0.001) compared with saline-treated controls.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 22

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

    Findingown data

    There was no change in amount consumed between home day and novel test day.

    “There was no change in amount consumed between home day and novel test day (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Long-term administration of ABT-089, but not ABT-107, during nicotine withdrawal significantly decreases latency to consume compared with animals undergoing 7-day withdrawal from nicotine.

    “However, long-term administration of ABT-089, but not ABT-107, during nicotine withdrawal showed a significant decrease in latency to consume compared with animals undergoing 7-day withdrawal from nicotine (Fig. 2B).”
    • Also stated in: § Discussion · plain
      “However, it is effective in alleviating anxiety during withdrawal (Fig. 2B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In drug-naive animals, long-term ABT-089 administration fails to produce an anxiolytic effect, unlike long-term nicotine administration.

    “In addition, unlike the decrease in latency observed with long-term nicotine administration (Fig. 1B), ABT-089 administration fails to produce an anxiolytic effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Long-term ABT-089 administration in drug-naive animals does not upregulate nAChRs, similar to its effects in nicotine-dependent animals.

    “Additionally, our findings from [ 3 H]EB binding assays demonstrate that long-term ABT-089 administration in drug-naive animals does not upregulate nAChRs (Fig. 4), similar to its effects in nicotine-dependent animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Although the ligand binding results are similar in drug-naive and drug-experienced animals exposed to long-term administration of ABT-089, their behavioral profiles are strikingly different.

    “However, although the ligand binding results are similar in drug-naive and drug-experienced animals exposed to long-term administration of ABT-089, their behavioral profiles are strikingly different.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    ABT-089 mediates its effects without upregulating nAChRs, a hallmark of sustained nAChR activation with nicotine.

    “Additionally, ABT-089 mediates its effects without upregulating nAChRs, a hallmark of sustained nAChR activation with nicotine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Short-term but not long-term administration of varenicline reduces anxiety during withdrawal.

    “Specifically, short-term but not long-term administration of varenicline reduces anxiety during withdrawal.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Turner et al., 2010 source

      Not checked in the free run.

    • cites Turner et al., 2013b

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    • cites Cinciripini et al., 2013 source

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  • May combine two claims.

    Interpretationown data

    Short-term administrations of ABT-089 and ABT-107 alleviate anxiety during nicotine withdrawal; however, only ABT-089 is effective in alleviating anxiety after long-term administration.

    “Short-term administrations of ABT-089 and ABT-107 alleviate anxiety during nicotine withdrawal; however, only ABT-089 is effective in alleviating anxiety after long-term administration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The NIH test is sensitive to the anxiolytic effect of long-term nicotine and the anxiogenic effect of 24-hour withdrawal from nicotine.

    “The NIH test is sensitive to the anxiolytic effect of long-term nicotine (Turner et al., 2010(Turner et al., , 2013b) ) and the anxiogenic effect of 24-hour withdrawal from nicotine (as shown in Fig. 1).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Turner et al., 2010 source

      Not checked in the free run.

    • cites Turner et al., 2013b

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  • May combine two claims.

    Premisecitation

    The NIH paradigm is a sensitive measure for potential anxiolytic drugs and anxiogenic effects of withdrawal on both acute and extended drug administration paradigms.

    “The NIH paradigm is a sensitive measure for potential anxiolytic drugs and anxiogenic effects of withdrawal on both acute and extended drug administration paradigms (Dulawa et al., 2004;Dulawa and Hen, 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dulawa et al., 2004 source

      Not checked in the free run.

    • cites Dulawa and Hen, 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, although most reports of anxiety occur during the first 24 hours, a return to baseline can take up to 4 weeks.

    “In humans, although most reports of anxiety occur during the first 24 hours, a return to baseline can take up to 4 weeks (Hughes, 1992).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hughes, 1992 source

      Not checked in the free run.

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

    Study design and conductnone given

    Mice were randomly assigned to treatment conditions and tested in counterbalanced order.

    “All experimental testing sessions were conducted between 9:00 AM and 1:00 PM, with animals randomly assigned to treatment conditions and tested in counterbalanced order.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    ABT-089 has been used successfully in patients with Alzheimer's disease and attention deficit disorder, with few unintended side effects.

    “ABT-089 has been rigorously studied as a treatment of cognitive disorders and has been used successfully in patients with Alzheimer's disease and attention deficit disorder, with few unintended side effects (Lin et al., 1997;Rueter et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lin et al., 1997 source

      Not checked in the free run.

    • cites Rueter et al., 2004 source

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    Premisecitation

    Both ABT-089 and ABT-107 enhance learning in naive animals.

    “Both ABT-089 and ABT-107 enhance learning in naive animals (Decker et al., 1997;Bitner et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Decker et al., 1997 source

      Not checked in the free run.

    • cites Bitner et al., 2010 source

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

    Premisecitation

    Varenicline is currently the best in class treatment of smoking cessation.

    “Varenicline (Chantix; Pfizer, Groton, CT), a partial agonist at a4b2 nicotinic acetylcholine receptors (nAChRs) and a full agonist at a7 and a3b4 nAChRs is currently the best in class treatment of smoking cessation (Coe et al., 2005;Garrison and Dugan, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Coe et al., 2005 source

      Not checked in the free run.

    • cites Garrison and Dugan, 2009

      Not checked in the free run.

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

    Premisecitation

    Nicotine is the major addictive component in tobacco and plays a critical role in initial tobacco reinforcement and dependence.

    “Nicotine, which is the major addictive component in tobacco, plays a critical role in initial tobacco reinforcement and dependence (Le Foll and Goldberg, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Le Foll and Goldberg, 2006

      Not checked in the free run.

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

    Premisecitation

    The heteromeric a4b2* subtype and the homomeric a7 are the most prevalent receptor subtypes in the central nervous system.

    “The heteromeric a4b2* subtype and the homomeric a7 are the most prevalent receptor subtypes in the central nervous system (Court et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Court et al., 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Withdrawal symptoms include difficulty concentrating, increased craving, depressed mood, and increased anxiety.

    “These symptoms include difficulty concentrating, increased craving, depressed mood, and increased anxiety (Hughes, 1992(Hughes, , 2007)).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hughes, 1992 source

      Not checked in the free run.

    • cites Hughes, 2007 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Long-term nicotine exposure produces a region-specific upregulation of b2-containing nAChRs.

    “Long-term nicotine exposure produces a region-specific upregulation of b2-containing nAChRs.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Wonnacott, 1990 source

      Not checked in the free run.

    • cites Marks et al., 1992 source

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    • cites Buisson and Bertrand, 2002 source

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

    Premisecitation

    a7 nAChRs are necessary in the ventral tegmental area for the expression of withdrawal from nicotine.

    “Furthermore, although a7 nAChRs have not been implicated directly in anxiety (Paylor et al., 1998;Vicens et al., 2011) they are necessary in the ventral tegmental area for the expression of withdrawal from nicotine, suggesting that targeting of the a7 subtype may also relieve nicotine withdrawal symptoms (Nomikos et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nomikos et al., 1999 source

      Not checked in the free run.

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

    Premisecitation

    ABT-107 has low incidence of side effects at varying doses in patients.

    “ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole; structure in Bitner et al., 2010] is a selective agonist with high affinity at a7 nAChRs that has been characterized as a cognitive enhancer in animal models of Alzheimer's disease and has low incidence of side effects at varying doses in patients (Bitner et al., 2010;Malysz et al., 2010;Othman et al., 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bitner et al., 2010 source

      Not checked in the free run.

    • cites Malysz et al., 2010 source

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    • cites Othman et al., 2011 source

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

    Premisecitation

    Varenicline acts at both a4b2* and a7 subtypes.

    “Varenicline, the best in class medication for smoking cessation, acts at both of these subtypes (Coe et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Coe et al., 2005 source

      Not checked in the free run.

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

    Premisecitation

    a7 nAChRs have not been implicated directly in anxiety.

    “Furthermore, although a7 nAChRs have not been implicated directly in anxiety (Paylor et al., 1998;Vicens et al., 2011) they are necessary in the ventral tegmental area for the expression of withdrawal from nicotine, suggesting that targeting of the a7 subtype may also relieve nicotine withdrawal symptoms (Nomikos et al., 1999).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Paylor et al., 1998 source

      Not checked in the free run.

    • cites Vicens et al., 2011 source

      Not checked in the free run.

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

    Premisecitation

    [3H]EB is a high-affinity ligand for all heteromeric nAChRs with low nonspecific binding.

    “[ 3 H]EB is a high-affinity ligand for all heteromeric nAChRs with low nonspecific binding (Badio and Daly, 1994).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Badio and Daly, 1994

      Not checked in the free run.

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

    Premisecitation

    Nicotine exerts its biologic effects through activation of central nAChRs that exist as subtypes determined by a and b subunit compositions.

    “Nicotine exerts its biologic effects through activation of central nAChRs that exist as subtypes determined by a and b subunit compositions (Gotti and Clementi, 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gotti and Clementi, 2004

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Long-term exposure to varenicline upregulates nAChRs.

    “Long-term exposure to varenicline upregulates nAChRs, which parallels its anxiolytic effects during cessation from nicotine (Turner et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Turner et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    b2 knockout mice, bereft of a4b2* heterodimers, have reduced anxiety during withdrawal from long-term nicotine and after mecamylamine precipitated withdrawal from nicotine.

    “Additionally, b2 knockout mice and, therefore, bereft of a4b2* heterodimers have reduced anxiety during withdrawal from long-term nicotine and after mecamylamine precipitated withdrawal from nicotine (Jackson et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jackson et al., 2008 source

      Not checked in the free run.

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

    Premisecitation

    a7 nAChRs do not appear to be necessary for somatic signs of withdrawal.

    “To date, a7 nAChRs have not been implicated in anxiety during nicotine withdrawal (Vicens et al., 2011), and they do not appear to be necessary for somatic signs of withdrawal (Markou and Paterson, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Markou and Paterson, 2001

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    ABT-089 functionally reduces anxiety during nicotine withdrawal without maintaining upregulation of heteromeric nAChRs.

    “These findings suggest that ABT-089 functionally reduces anxiety during nicotine withdrawal without maintaining upregulation of heteromeric nAChRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In contrast to varenicline, ABT-089 allows nAChRs to downregulate back to saline levels while providing an anxiolytic effect during withdrawal from nicotine.

    “Therefore, in contrast to varenicline, ABT-089 allows nAChRs to downregulate back to saline levels while providing an anxiolytic effect during withdrawal from nicotine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A previous study showed ABT-089 decreased anxiety after short-term rather than long-term administration.

    “Although a previous study showed ABT-089 decreased anxiety, this was after short-term rather than long-term administration (Lin et al., 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lin et al., 1997 source

      Not checked in the free run.

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

    Interpretationreasoning

    Findings from this study suggest a complex association between nAChR regulation and behavior.

    “Finally, findings from this study suggest a complex association between nAChR regulation and behavior.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    This study is the first to demonstrate that the selective partial nAChR agonist ABT-089 reduces anxiety during nicotine withdrawal without maintaining the upregulated pool of heteromeric nAChRs.

    “This study is the first to demonstrate that the selective partial nAChR agonist ABT-089 reduces anxiety during nicotine withdrawal without maintaining the upregulated pool of heteromeric nAChRs.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ABT-089 is a selective partial agonist at a4b2*/a6* nAChRs.

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

    Interpretationown data

    Targeting of a7 nAChRs may relieve withdrawal symptoms by activating nAChRs in the absence of nicotine.

    “However, as short-term ABT-107 reduced latency to consume during nicotine withdrawal, the targeting of a7 nAChRs may relieve withdrawal symptoms by activating nAChRs in the absence of nicotine.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    To date, a7 nAChRs have not been implicated in anxiety during nicotine withdrawal.

    “To date, a7 nAChRs have not been implicated in anxiety during nicotine withdrawal (Vicens et al., 2011), and they do not appear to be necessary for somatic signs of withdrawal (Markou and Paterson, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vicens et al., 2011 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The upregulated pool of nAChRs arising from long-term exposure to nicotine may drive elements of the nicotine withdrawal syndrome.

    “Previous studies suggest that the upregulated pool of nAChRs arising from long-term exposure to nicotine may drive elements of the nicotine withdrawal syndrome (Turner et al., 2011;Gould et al., 2012), and this protracted upregulation of nAChRs has been correlated with reduced ability to maintain abstinence in the clinical population (Staley et al., 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Turner et al., 2011 source

      Not checked in the free run.

    • cites Gould et al., 2012 source

      Not checked in the free run.

36 of 36

  • The paper relies on this without support.

    ABT-089 and ABT-107 have not been evaluated for their role in reducing anxiety after nicotine withdrawal or regulation of nAChRs.

    “However, ABT-089 and ABT-107 have not been evaluated for their role in reducing anxiety after nicotine withdrawal or regulation of nAChRs.”

  • The paper relies on this without support.

    Mouse NIH results translate to human nicotine withdrawal anxiety and treatment efficacy.

    “Therefore, the efficacy of ABT-089 to reduce anxiety within an extended time period suggests that it would be an effective treatment of the alleviation of both the initial anxiety experienced during withdrawal (Fig. 1) as well as anxiety over the course of abstinence.”

  • The paper relies on this without support.

    ABT-089 is a selective partial agonist at a4b2*/a6* nAChRs.

    “This study is the first to demonstrate that the selective partial nAChR agonist ABT-089 reduces anxiety during nicotine withdrawal without maintaining the upregulated pool of heteromeric nAChRs.”

  • The paper relies on this without support.

    ABT-107 is a selective partial agonist at a7 nAChRs.

    “Interestingly, ABT-107, a selective partial agonist at a7 nAChRs is capable of alleviating anxiety at 24-hour withdrawal from nicotine, but not after extended administration, suggesting the role of several types of nAChRs in the initial withdrawal symptoms after nicotine cessation that may differ when withdrawal is extended.”

  • The paper relies on this without support.

    Observations of increased anxiety during nicotine withdrawal are generally evident during the first 24 to 72 hours.

    “However, these observations are generally evident during the first 24 to 72 hours of nicotine withdrawal.”
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?

  • Desensitization of α7 nAChRs by the α7 partial agonist ABT-107 reversed the anxiogenic effects of nicotine withdrawal.

    “desensitization of α7 nAChRs by using an α7 partial agonist, ABT-107, was found to reverse the anxiogenic effects of nicotine withdrawal (Yohn et al., 2014).”

    From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Yohn et al., 2014

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.

  • ABT-089 is called anxiogenic in naive animals despite no significant treatment effect

    Major

    The abstract describes ABT-089 as anxiogenic in nicotine-naive animals, but the results report no treatment effect and say the apparent increase in latency was nonsignificant.

  • Figure 5 calls withdrawal from ABT-089 nicotine withdrawal

    Minor

    The figure caption says the mice received ABT-089 or saline, but describes removal of the ABT-089 minipumps as inducing nicotine withdrawal.

  • Short-term varenicline is said both to reduce and to fail to alleviate withdrawal anxiety

    Minor

    The discussion says short-term varenicline reduces anxiety during withdrawal, then says short-term varenicline during nicotine withdrawal fails to alleviate anxiety-like behavior.

3 of 3

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Authors
Yohn, N. L., Turner, J. R., & Blendy, J. A.
Affiliations
University of Pennsylvania (US)
ORCID
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2014-05
Volume
349
Issue
2
Pages
348-354
ISSN
0022-3565 (ISSN-L)
DOI
10.1124/jpet.113.211706
PMC
PMC3989801
OpenAlex
W2166251811
Semantic Scholar
53368b1d2af0246497322b563063731f08728ea8
Cited by
28
References
54
Citations by year
2024: 2 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 9 · 2014: 2
FWCI
2.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute on Drug Abuse (R00DA032681, T32 DA28874, K99DA032681, T32DA028874)
  • National Cancer Institute (CA-143187, P50CA143187)
  • National Institute on Minority Health and Health Disparities (L60 MD006479)
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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
nicotinic acetylcholine receptors, alpha4beta2 nicotinic receptor, nicotine withdrawal, anxiety, varenicline, partial agonists, nicotine cessation, novelty-induced hypophagia, receptor up-regulation, smoking cessation aids, anxiogenic effects
MeSH terms
Animals, Anxiety, Brain, Indoles, Male, Nicotine, Pyridines, Pyrrolidines, Quinuclidines, Radioligand Assay, Receptors, Nicotinic, Substance Withdrawal Syndrome, Time Factors, Anti-Anxiety Agents, Up-Regulation, Nicotinic Agonists, Mice, Drug Partial Agonism

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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