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Cited by 66Smoking Behavior and CessationNicotinic Acetylcholine Receptors StudyPrenatal Substance Exposure Effects

Mechanistic insights into nicotine withdrawal

Open access
Paolini, Michael, De Biasi, Mariella·2011·Biochemical Pharmacology
DOI 10.1016/j.bcp.2011.07.075PMC PMC3312005
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Abstract

Smoking is responsible for over 400,000 premature deaths in the United States every year, making it the leading cause of preventable death. In addition, smoking-related illness leads to billions of dollars in healthcare expenditures and lost productivity annually. The public is increasingly aware that successfully abstaining from smoking at any age can add years to one’s life and reduce many of the harmful effects of smoking. Although the majority of smokers desire to quit, only a small fraction of attempts to quit are actually successful. The symptoms associated with nicotine withdrawal are a primary deterrent to cessation and they need to be quelled to avoid early relapse. This review will focus on the neuroadaptations caused by chronic nicotine exposure and discuss how those changes lead to a withdrawal syndrome upon smoking cessation. Besides examining how nicotine usurps the endogenous reward system, we will discuss how the habenula is part of a circuit that plays a critical role in the aversive effects of high nicotine doses and nicotine withdrawal. We will also provide an updated summary of the role of various nicotinic receptor subtypes in the mechanisms of withdrawal. This growing knowledge provides mechanistic insights into current and future smoking cessation therapies.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes neuroadaptations from chronic nicotine and how their disruption produces withdrawal, emphasizing dopaminergic hypofunction, habenula/MHb-IPN anti-reward circuitry, and nAChR subtype-specific mechanisms. It also reviews current and emerging cessation pharmacotherapies, including NRT, bupropion, varenicline, and nicotine vaccines.

Key findings

  • Smoking causes 443,000 premature US deaths/year and about $96 billion in healthcare costs plus $97 billion in lost productivity; 21% of adults smoke, 70% want to quit, but only 3% succeed annually; quitting at 35 adds about 8 years of life.
  • Withdrawal is linked to decreased mesolimbic DA activity and increased DA reuptake; CRF increases by >500% in the CeA after mecamylamine-precipitated withdrawal, and a CRF1 antagonist in the CeA blunts anxiety-like behavior.
  • Somatic withdrawal requires MHb/IPN nAChRs containing α2, α5, and/or β4; β2- and α6-containing nAChRs are necessary for CPA and withdrawal-induced anxiety, while α5/α7 are not required for CPA; α4β2 but not α7 receptors are implicated in withdrawal attention deficits.
  • Pharmacotherapy: NRT roughly doubles quit rates; 12-month abstinence is 5.3% vs 2.6% placebo in smokers unwilling to attempt abrupt quit and about 16% vs 10% in those willing; bupropion yields 14–18%, rising to 29% with NRT; varenicline yields 21–23% at 52 weeks vs bupropion 14–16% and placebo 8–10%. A nicotine vaccine reduced brain nicotine by 90% after 10-min nose-only smoke exposure and 35% after 2-h whole-body exposure in rats.

Methods

  • Narrative review; no primary data or systematic search/meta-analysis described. It synthesizes preclinical and clinical literature on nicotine dependence, withdrawal neurobiology, animal models, and cessation pharmacotherapy.
  • Animal models discussed include spontaneous and mecamylamine-precipitated withdrawal, somatic sign scoring, intracranial self-stimulation, conditioned place aversion, elevated plus maze/open field/light-dark box, fear conditioning, and five-choice serial reaction time task.
  • Main analysis is qualitative integration of pharmacological, nAChR mutant mouse, lentiviral re-expression, microdialysis, and human trial findings.

Limitations

  • Stated: understanding of circuits/molecular mechanisms for aversive stimuli, including high nicotine doses, is still limited; influence of nAChR subtypes on withdrawal-induced anxiety has not been examined exhaustively; whether a nicotine vaccine will be effective in real-world use remains open; serious adverse-event causal relationship for bupropion/varenicline has not been established.
  • Evident: as a narrative review, it lacks systematic search/quality appraisal and does not quantify effect sizes beyond cited trials; much mechanistic evidence comes from rodent models, and human withdrawal symptom time course is reported as inconsistent (peak first week, taper 3–4 weeks, but some reports 10 days or >31 days).

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

Integrity signals

Registry

Crossref · 10.1016/j.bcp.2011.07.075

Cites

298 of 298 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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    ACh released in the VTA promotes the switch between tonic and phasic DAergic activity that signals reward and salience.

    “The cholinergic system exerts a profound effect on DAergic activity as ACh released in the VTA promotes the switch between tonic and phasic activity in DAergic neurons that signals reward and salience [38, 39].”
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  • Premisecitation

    Changes in DAergic activity can signal punishment, aversion, or lack of expected reward, not only hedonic effects.

    “Although it was originally postulated that the DA released from the VTA only mediates the hedonic or pleasurable effects of natural reinforcers, it is now clear that changes in DAergic activity can also signal punishment, aversion, or lack of expected reward [53–58].”
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  • Interpretationreasoning

    Smoking cessation disrupts the equilibrium maintained by nicotine and leads to withdrawal manifestations.

    “Smoking cessation disrupts the equilibrium maintained in the presence of nicotine and leads to the manifestations of withdrawal.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Chronic nicotine exposure causes neuroadaptations that produce widespread changes in brain neurotransmission, promoting and sustaining tobacco use.

    “The neuroadaptations arising from chronic nicotine exposure cause widespread alterations in brain neurotransmission that promote and sustain the use of tobacco [21–24].”
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  • Premisecitation

    Blocking cholinergic transmission in the MHb or IPN precipitates somatic signs of nicotine withdrawal.

    “Additionally, blocking cholinergic transmission in either the MHb or IPN is sufficient to precipitate somatic signs of nicotine withdrawal [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims. 40
  • Classified as probably not a substantial claim. 3

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    Premisecitation

    The DAergic system, particularly the mesocorticolimbic pathway, is involved in drug addiction because DA modulates limbic and cortical sites for goal-directed behavior.

    “The role of the DAergic system (in particular the mesocorticolimbic pathway) in drug addiction derives from DA’s ability to modulate many of the limbic and cortical sites involved in goal-directed behavior (Fig. 1) [18, 28–31].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
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  • May combine two claims.

    Premisecitation

    Addictive drugs including nicotine hijack experience-dependent adaptive mechanisms and cause abnormally high DA levels.

    “Addictive drugs, including nicotine, hijack the mechanisms of experience-dependent adaptive behavior and lead to abnormally high DA levels [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a given year, only 3% of smokers successfully quit, while 70% express a desire to quit.

    “However, in a given year, only 3% of smokers are actually successful in their cessation attempts, even though 70% of smokers express desire to quit [6].”
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    Premisecitation

    Nicotine withdrawal symptoms are a primary reason smokers fail to quit and must be alleviated to prevent early relapse.

    “The symptoms associated with nicotine withdrawal are a primary deterrent to cessation and they need to be quelled to avoid early relapse.”
    • Also stated in: § 1 Introduction · boosted
      “The symptoms associated with the nicotine abstinence syndrome contribute to the maintenance of the smoking habit and are a potent deterrent for those who are trying to quit [25–27].”
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    Premisecitation

    Neuronal nAChR upregulation is an important adaptive change and a major contributor to nicotine's addictive properties.

    “Neuronal nAChR upregulation is an important adaptive change and a major contributor to the addictive properties of nicotine [83–86].”
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    Premisecitation

    Nicotine self-administration decreases xCT in the NAcc and VTA and GLT-1 in the NAcc.

    “Nicotine self-administration also decreases expression of the cystine-glutamate exchanger, xCT, in the NAcc and VTA, and decreases the glial glutamate transporter, GLT-1, in the NAcc [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Nicotine withdrawal symptoms typically peak within the first week and taper over 3-4 weeks, though some reports say they subside within 10 days and others say they persist past 31 days.

    “Nicotine withdrawal symptoms are typically reported to reach a peak within the first week of abstinence and taper off for the next 3–4 weeks [119, 124]. However, some reports indicate that symptoms can subside within 10 days [125], while others indicate that withdrawal symptoms may persist past 31 days [126, 127].”
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    Interpretationcitation

    Chronic nicotine exposure likely causes global alterations in brain neurotransmission because nAChR activation affects release of virtually every major neurotransmitter.

    “As nAChR activation affects the release of virtually every major neurotransmitter [106, 117, 118], chronic nicotine exposure is likely to cause global alterations in brain neurotransmission.”
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  • May combine two claims.

    Premisecitation

    Seven nicotine withdrawal symptoms are validated and appear in DSM-IV-TR: irritability/anger/frustration, anxiety, depression/negative affect, concentration problems, impatience, insomnia, and restlessness.

    “Seven nicotine withdrawal symptoms were validated in a recent comprehensive review on the topic [119] and appear in the DSM-IV-TR [120]. The symptoms are irritability/anger/frustration, anxiety, depression/negative affect, concentration problems, impatience, insomnia, and restlessness.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    • cites [120] American Psychiatric Association Diagnostic and statistical manual of mental disorders 4 text revision ed 2000 Washington, D.C

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  • May combine two claims.

    Premisecitation

    nAChR upregulation varies by receptor subtype, brain region, and contingency of nicotine administration.

    “Relevant to the understanding of the neuroadaptations produced by nicotine is the fact that nAChR upregulation differs among receptor subtypes, varies among brain regions for the same subtype, and even depends on the contingency of nicotine administration [9, 90, 93].”
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    Premisecitation

    Nicotine desensitizes nAChRs, driving increased receptor levels as an attempt to maintain circuit homeostasis.

    “Nicotine desensitizes nAChRs and renders them unresponsive and this phenomenon drives an increase in receptor levels as part of an attempt to maintain circuit-level homeostasis [87–89].”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    Premisecitation

    The LHb is a source of anti-reward signals that influences reward-related DA neuron activity.

    “Studies conducted in recent years have identified the LHb as a source of anti-reward signals that plays an important role in determining the reward-related activity of DA neurons [18, 30, 68–70].”
    Quote in the paperSubstantial claim0 of 5 sources checked
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    • cites [30] Ikemoto S Brain reward circuitry beyond the mesolimbic dopamine system: A neurobiological theory Neuroscience & Biobehavioral Reviews 2010 35 2 129 150 20149820 PMC2894302 source

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

    Interpretationreasoning

    Withdrawal is a collection of affective and somatic symptoms that emerge hours after nicotine abstinence and reflect neurochemical imbalance from nicotine absence.

    “Withdrawal is a collection of affective and somatic symptoms that emerge a few hours after nicotine abstinence and reflect the imbalance in brain neurochemistry created by the absence of nicotine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Repeated nicotine exposure produces heterologous adaptations, including increased AMPA/NMDA current ratios at DA neurons and increased high-affinity D2 receptors in the NAcc.

    “Besides altering cholinergic function, repeated nicotine exposure produces heterologous adaptations. For example, nicotine increases AMPA/NMDA current ratios (a hallmark of long-term potentiation) at DA neurons [94–96] and other locations involved in drug-associated memory [97–99]. In the NAcc, nicotine leads to an increase in high affinity DA D2 receptors [100].”
    Quote in the paperSubstantial claim0 of 4 sources checked
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    Premisecitation

    Nicotine follows an inverted U-shaped dose-response curve, and smokers titrate intake to get rewarding effects while avoiding aversive effects of high doses.

    “Nicotine follows an inverted U-shaped dose-response curve [18, 60], and smokers titrate their nicotine intake to experience the rewarding while avoiding the aversive effects produced by high nicotine doses [61–64].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
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  • May combine two claims.

    Premisecitation

    α5-containing nAChRs in the MHb control the amount of nicotine self-administered, as α5−/− mice self-administer doses that normally cause aversion in wild type.

    “A recent report suggests that α5-containing nAChRs in the MHb are key to the control of the amounts of nicotine self-administered as α5−/− mice continue to self-administer nicotine at doses that normally elicit strong aversion in wild type animals [79, 80].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    • cites [80] Fowler CD Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake Nature 2011 471 7340 597 601 21278726 PMC3079537 source

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  • May combine two claims.

    Premisecitation

    Rodents chronically exposed to nicotine undergo a characteristic withdrawal syndrome that can occur spontaneously or be precipitated by mecamylamine.

    “Rodents chronically exposed to nicotine undergo a characteristic withdrawal syndrome which develops spontaneously, after removing the nicotine source, or can be precipitated by administration of a nAChR antagonist such as mecamylamine [7, 11, 81, 163–166].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
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    • cites [81] Salas R Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice J Neurosci 2009 29 10 3014 8 19279237 PMC3862238 source

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    • Rests on an assumption: Animal models of nicotine withdrawal are valid tools for understanding human nicotine withdrawal and for testing smoking cessation agents.
    • Rests on an assumption: The withdrawal syndrome observed in rodents corresponds to human nicotine withdrawal.

  • May combine two claims.

    Premisecitation

    β2-containing and α6-containing nAChRs are necessary for conditioned place aversion, but α5 and α7 do not affect it.

    “Pharmacological studies in nAChR null mice indicate that β2-containing and α6-containing nAChRs are necessary for CPA, but neither the α5, nor the α7 subunits affect CPA behavior [170, 172, 189].”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    • Rests on an assumption: Animal models of nicotine withdrawal are valid tools for understanding human nicotine withdrawal and for testing smoking cessation agents.
    • Rests on an assumption: The withdrawal syndrome observed in rodents corresponds to human nicotine withdrawal.

  • May combine two claims.

    Premisecitation

    The hypodopaminergic state during withdrawal is produced by reduced DA release and increased DA re-uptake due to DAT upregulation.

    “The hypodopaminergic state associated with withdrawal is produced by both a reduction in DA release and an increase in DA re-uptake [140]. Increased DA re-uptake is due to upregulation of the DA transporter (DAT) [137, 141].”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    • cites [141] Hadjiconstantinou M Enhanced dopamine transporter function in striatum during nicotine withdrawal Synapse 2011 65 2 91 8 20506223 source

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  • May combine two claims.

    Premisecitation

    Somatic withdrawal can be precipitated by mecamylamine microinjection into the MHb or IPN, but not into hippocampus, cortex, or VTA.

    “Somatic withdrawal can be precipitated by mecamylamine microinjection into the MHb or the IPN, but not into hippocampus, cortex, or VTA [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Salas R Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice J Neurosci 2009 29 10 3014 8 19279237 PMC3862238 source

      Not checked in the free run.

    • Rests on an assumption: Animal models of nicotine withdrawal are valid tools for understanding human nicotine withdrawal and for testing smoking cessation agents.
    • Rests on an assumption: The withdrawal syndrome observed in rodents corresponds to human nicotine withdrawal.

  • May combine two claims.

    Premisecitation

    Bupropion may increase NE levels in the dorsal raphe nucleus, leading to increased 5-HT levels.

    “The drug may also function by increasing NE levels in the dorsal raphe nucleus, thus leading to increased serotonin (5-HT) levels [217].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] El Mansari M Sustained administration of bupropion alters the neuronal activity of serotonin, norepinephrine but not dopamine neurons in the rat brain Neuropharmacology 2008 55 7 1191 8 18708076 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bupropion is an atypical antidepressant and smoking cessation aid that targets multiple neurotransmitter systems.

    “Bupropion is an atypical antidepressant and smoking cessation aid that exerts its actions by targeting multiple neurotransmitter systems [214].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Dwoskin LP Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent CNS Drug Rev 2006 12 3–4 178 207 17227286 PMC6506196

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The enhancement of fear conditioning by nicotine requires β2-containing but not α7-containing nAChRs.

    “This enhancement by nicotine requires β2-containing but not α7-containing nAChRs [199].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Davis JA Gould TJ beta2 subunit-containing nicotinic receptors mediate the enhancing effect of nicotine on trace cued fear conditioning in C57BL/6 mice Psychopharmacology (Berl) 2007 190 3 343 52 17136517 PMC2722435 source

      Not checked in the free run.

    • Rests on an assumption: Animal models of nicotine withdrawal are valid tools for understanding human nicotine withdrawal and for testing smoking cessation agents.
    • Rests on an assumption: The withdrawal syndrome observed in rodents corresponds to human nicotine withdrawal.

  • May combine two claims.

    Premisecitation

    Nicotine enhances hippocampus-dependent contextual and cued trace fear conditioning, but not cued delay fear conditioning.

    “Nicotine is known to enhance hippocampus-dependent contextual and cued trace fear conditioning, but not cued delay fear conditioning [198].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [198] Gould TJ Feiro O Moore D Nicotine enhances trace cued fear conditioning but not delay cued fear conditioning in C57BL/6 mice Behav Brain Res 2004 155 1 167 73 15325790 source

      Not checked in the free run.

    • Rests on an assumption: Animal models of nicotine withdrawal are valid tools for understanding human nicotine withdrawal and for testing smoking cessation agents.
    • Rests on an assumption: The withdrawal syndrome observed in rodents corresponds to human nicotine withdrawal.

  • May combine two claims.

    Premisecitation

    Systemic NMDA receptor antagonists inhibit acquisition of contextual fear conditioning, and this effect is ameliorated by nicotine acting at α4β2-containing nAChRs.

    “Also, systemic administration of NMDA receptor antagonists inhibits acquisition of contextual fear conditioning [200]. This effect is ameliorated by co-administration of systemic nicotine acting at α4β2-containing nAChRs, as indicated by antagonism with DHβE [200].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Andre JM Leach PT Gould TJ Nicotine ameliorates NMDA receptor antagonist-induced deficits in contextual fear conditioning through high-affinity nicotinic acetylcholine receptors in the hippocampus Neuropharmacology 2011 60 4 617 25 21167848 PMC3031743 source

      Not checked in the free run.

    • Rests on an assumption: Animal models of nicotine withdrawal are valid tools for understanding human nicotine withdrawal and for testing smoking cessation agents.
    • Rests on an assumption: The withdrawal syndrome observed in rodents corresponds to human nicotine withdrawal.

  • May combine two claims.

    Premisecitation

    The 5-CSRTT is a visual attention task that can reliably detect cognitive aspects of nicotine withdrawal.

    “The five-choice serial reaction time task (5-CSRTT) is a visual attention task [205] that can reliably detect cognitive aspects of nicotine withdrawal [206, 207].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [205] Grottick AJ Higgins GA Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task Behav Brain Res 2000 117 1–2 197 208 11099773 source

      Not checked in the free run.

    • cites [206] Shoaib M Bizarro L Deficits in a sustained attention task following nicotine withdrawal in rats Psychopharmacology (Berl) 2005 178 2–3 211 22 15338107 source

      Not checked in the free run.

    • cites [207] Semenova S I Stolerman P Markou A Chronic nicotine administration improves attention while nicotine withdrawal induces performance deficits in the 5-choice serial reaction time task in rats Pharmacol Biochem Behav 2007 87 3 360 8 17582477 PMC2691389 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    α4β2-containing nAChRs, but not α7-containing nAChRs, are important for 5-CSRTT performance.

    “suggesting that α4β2-containing, but not α7-containing nAChRs are important for 5-CSRTT.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [206] Shoaib M Bizarro L Deficits in a sustained attention task following nicotine withdrawal in rats Psychopharmacology (Berl) 2005 178 2–3 211 22 15338107 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    β2 and α6 nAChR subunits are necessary for increased anxiety during withdrawal, whereas α5 and α7 may not be required.

    “So far, it has been established that the β2 and α6 nAChR subunits are necessary for increased anxiety during withdrawal [170, 172], whereas, α5 and α7 may not be required [170].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [170] Jackson KJ Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs J Pharmacol Exp Ther 2008 325 1 302 12 18184829 PMC3821841 source

      Not checked in the free run.

    • cites [172] Jackson KJ The role of alpha6-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal J Pharmacol Exp Ther 2009 331 2 547 54 19644040 PMC2775251 source

      Not checked in the free run.

    • Rests on an assumption: Animal models of nicotine withdrawal are valid tools for understanding human nicotine withdrawal and for testing smoking cessation agents.
    • Rests on an assumption: The withdrawal syndrome observed in rodents corresponds to human nicotine withdrawal.

  • May combine two claims.

    Premisecitation

    Both nicotine and bupropion serve as primary reinforcers in non-human subjects.

    “both nicotine and bupropion serve as primary reinforcers in non-human subjects [228]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Chaudhri N Operant responding for conditioned and unconditioned reinforcers in rats is differentially enhanced by the primary reinforcing and reinforcement-enhancing effects of nicotine Psychopharmacology (Berl) 2006 189 1 27 36 17019569 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gonzales and colleagues found a similar decrease in negative affect, but also a significant decrease in restlessness in patients taking varenicline.

    “Gonzales and colleagues [241] found a similar decrease in negative affect, but also found a significant decrease in restlessness in patients taking varenicline.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241] Gonzales D Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial JAMA 2006 296 1 47 55 16820546 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Varenicline acts as a partial agonist at α3β4-, α2-, and α6-containing nAChRs, and a full agonist at α7 nAChRs.

    “It acts as a partial agonist at α3β4-, α2-, and α6-containing nAChRs, and a full agonist at α7 nAChRs [238].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [238] Mihalak KB Carroll FI Luetje CW Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors Mol Pharmacol 2006 70 3 801 5 16766716 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both bupropion and nicotine increase catecholamine concentrations in midbrain limbic regions.

    “both increase catecholamine concentrations in midbrain limbic regions [214, 227].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [214] Dwoskin LP Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent CNS Drug Rev 2006 12 3–4 178 207 17227286 PMC6506196 source

      Not checked in the free run.

    • cites [227] Balfour DJ The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence Behav Brain Res 2000 113 1–2 73 83 10942034 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both bupropion and nicotine are psychomotor stimulants.

    “Both drugs are psychomotor stimulants [225, 226]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [225] Bevins RA Palmatier MI Nicotine-conditioned locomotor sensitization in rats: assessment of the US-preexposure effect Behav Brain Res 2003 143 1 65 74 12842297 source

      Not checked in the free run.

    • cites [226] Wilkinson JL Bevins RA Bupropion hydrochloride produces conditioned hyperactivity in rats Physiol Behav 2007 90 5 790 6 17300819 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Varenicline is a derivative of cytisine, a plant alkaloid with selective affinity and partial agonism for α4β2 nAChRs.

    “It is a derivative of cytisine, a plant alkaloid with selective affinity and partial agonism for α4β2 nAChRs [236–238].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [236] Luetje CW Patrick J Both alpha- and beta-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors J Neurosci 1991 11 3 837 45 1705971 PMC6575344 source

      Not checked in the free run.

    • cites [237] Papke RL Heinemann SF Partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta 2 subunit Mol Pharmacol 1994 45 1 142 9 8302273 source

      Not checked in the free run.

    • cites [238] Mihalak KB Carroll FI Luetje CW Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors Mol Pharmacol 2006 70 3 801 5 16766716 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both nicotine and bupropion increase responding for reinforcing non-drug stimuli.

    “and increase responding for reinforcing non-drug stimuli [229–231].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [229] Chaudhri N Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement Psychopharmacology (Berl) 2006 184 3–4 353 66 16240165 source

      Not checked in the free run.

    • cites [230] Palmatier MI Bupropion and nicotine enhance responding for nondrug reinforcers via dissociable pharmacological mechanisms in rats Psychopharmacology (Berl) 2009 207 3 381 90 19760281 PMC2884399 source

      Not checked in the free run.

    • cites [231] Robbins TW Relationship between reward-enhancing and stereotypical effects of psychomotor stimulant drugs Nature 1976 264 5581 57 9 12471 source

      Not checked in the free run.

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

    Interpretationnone given

    Chronic exposure to nicotine produces neuroadaptations in a host of neurotransmitter and neuropeptide systems.

    “Chronic exposure to nicotine produces neuroadaptations in a host of neurotransmitter and neuropeptide systems.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Anti-nicotine antibodies bind nicotine with high affinity and specificity, preventing or at least slowing nicotine's entry into the brain.

    “Anti-nicotine antibodies will bind to nicotine with high affinity and specificity, thus preventing or at least slowing nicotine’s entry into the brain [247].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [247] Kosten T Owens SM Immunotherapy for the treatment of drug abuse Pharmacol Ther 2005 108 1 76 85 16023218 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Those neuroadaptations are responsible for the psychological and behavioral symptoms associated with nicotine abstinence and make nicotine addiction hard to break.

    “Those neuroadaptations are responsible for the psychological and behavioral symptoms associated with nicotine abstinence and make nicotine addiction so hard to break.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The 52-week abstinence rate for NRT was 20.4%, higher than most previously reported rates, while varenicline maintained the usual reported rate (26.1%).

    “the 52 week abstinence rate for NRT was found to be 20.4%, higher than most previously reported rates, while varenicline maintained the usual reported rate (26.1%) [242].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Aubin HJ Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial Thorax 2008 63 8 717 24 18263663 PMC2569194 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early phase 1/2 clinical trials in humans have demonstrated drug safety, effective immunogenicity, and promising increases in abstinence rates, especially among individuals with higher levels of anti-nicotine IgGs.

    “Early phase 1/2 clinical trials in humans have demonstrated drug safety, effective immunogenicity, and promising increases in abstinence rates, especially among individuals with higher levels of anti-nicotine IgGs [253–256].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [253] Cornuz J A vaccine against nicotine for smoking cessation: a randomized controlled trial PLoS One 2008 3 6 e2547 18575629 PMC2432028 source

      Not checked in the free run.

    • cites [254] Wagena EJ The immunogenicity and safety of a nicotine vaccine in smokers and nonsmokers: results of a randomized, placebo-controlled phase 1/2 trial Nicotine Tob Res 2008 10 1 213 8 18188762 source

      Not checked in the free run.

    • cites [255] Hatsukami DK Safety and immunogenicity of a nicotine conjugate vaccine in current smokers Clin Pharmacol Ther 2005 78 5 456 67 16321612 source

      Not checked in the free run.

    • cites [256] Maurer P A therapeutic vaccine for nicotine dependence: preclinical efficacy, and Phase I safety and immunogenicity Eur J Immunol 2005 35 7 2031 40 15971275 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreasing the rate of absorption and the actions of an addictive drug on its targets reduce its rewarding effects and may aid in quitting.

    “Decreasing the rate of absorption and the actions of an addictive drug on its targets reduce its rewarding effects and may aid in quitting [247, 248].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [247] Kosten T Owens SM Immunotherapy for the treatment of drug abuse Pharmacol Ther 2005 108 1 76 85 16023218 source

      Not checked in the free run.

    • cites [248] Swanson JM Volkow ND Pharmacokinetic and pharmacodynamic properties of stimulants: implications for the design of new treatments for ADHD Behav Brain Res 2002 130 1–2 73 8 11864720 source

      Not checked in the free run.

41 of 41

  • The paper relies on this without support.

    Nicotine is the major addictive component of tobacco.

    “Nicotine, the major addictive component of tobacco, binds to nicotinic acetylcholine receptors (nAChR).”

  • The paper relies on this without support.

    Animal models of nicotine withdrawal are valid tools for understanding human nicotine withdrawal and for testing smoking cessation agents.

    “Animal models of nicotine deprivation are invaluable tools for the understanding of the molecular underpinning of nicotine withdrawal symptoms and provide a way to test potential smoking cessation agents.”

  • The paper relies on this without support.

    The withdrawal syndrome observed in rodents corresponds to human nicotine withdrawal.

    “Rodents chronically exposed to nicotine undergo a characteristic withdrawal syndrome which develops spontaneously, after removing the nicotine source, or can be precipitated by administration of a nAChR antagonist such as mecamylamine [7, 11, 81, 163–166].”

  • The paper relies on this without support.

    Withdrawal syndrome often produces effects opposite to those of acute or chronic drug use.

    “As with many effects of acute or chronic drug use, the withdrawal syndrome often results in an opposite effect.”

  • The paper relies on this without support.

    Nicotine enhances trace fear conditioning.

    “Since nicotine enhances trace fear conditioning, one could expect withdrawal to cause a deficit in the same paradigm.”

  • The paper relies on this without support.

    All current therapeutic strategies for smoking cessation address the hypodopaminergic state produced by withdrawal in the VTA.

    “All current therapeutic strategies, albeit with different mechanisms, address the hypodopaminergic state produced by withdrawal in the VTA.”

  • The paper relies on this without support.

    Nicotine undergoes first-pass metabolism in the liver, reducing oral bioavailability.

    “Because nicotine undergoes first pass metabolism in the liver, the bioavailability of nicotine administered per os is reduced.”

  • The paper relies on this without support.

    Long-term tobacco use causes morbidity in a high percentage of subjects and kills half of all long-term smokers.

    “Because long-term tobacco use causes morbidity in a high percentage of subjects and ends up killing half of all long-term smokers”

  • The paper relies on this without support.

    All previously described pharmacotherapies require compliance to maintain efficacy.

    “All the previously described pharmacotherapies require compliance to maintain efficacy.”
9 of 9

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?

  • Somatic withdrawal signs in mice include excessive grooming, chewing, tremors, wetdog shakes, yawns, and teeth chattering.

    “Somatic symptoms in mice include excessive grooming, chewing, tremors, “wetdog” shakes, yawns, and teeth chattering (Paolini and De Biasi 2011).”

    From Nicotine Withdrawal (2015) · cites this paper as Paolini and De Biasi 2011

    Section 3.3.1, “Somatic signs of withdrawal” (page not provided), lists chewing, teeth-chattering, shakes, tremors, and yawns as somatic signs in rodents and discusses somatic withdrawal in mice. It does not mention excessive grooming or specify that the shakes are “wetdog” shakes. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

14 of the 312 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Salas, 2009, Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice, J Neurosci, 3014, 10.1523/jneurosci.4934-08.2009 · DOI · Paper page
  2. Damaj, 2003, Characterization of spontaneous and precipitated nicotine withdrawal in the mouse, J Pharmacol Exp Ther, 10.1124/jpet.103.054908 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Paolini, M., & De Biasi, M.
Affiliations
Baylor College of Medicine (US)
Venue
Biochemical Pharmacology
Publisher
Elsevier BV
Published
2011-10
Volume
82
Issue
8
Pages
996-1007
ISSN
0006-2952 (ISSN-L)
DOI
10.1016/j.bcp.2011.07.075
PMC
PMC3312005
OpenAlex
W1966522699
Semantic Scholar
2261425ac8e6d26e804aba9bb019d50b42420ff6
Cited by
66
References
312
Citations by year
2026: 1 · 2025: 6 · 2023: 7 · 2021: 7 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 6 · 2014: 9 · 2013: 10 · 2012: 4
FWCI
0.82
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochemical Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Drug Abuse (DA017173, DA024385)
  • National Cancer Institute (U19 CA148127)
  • Cancer Prevention Institute of Texas (RP100443, RP101120)
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 withdrawal, smoking cessation, chronic nicotine exposure, neural adaptation, habenula, nicotinic receptor subtypes, relapse, smoking cessation therapy
MeSH terms
Animals, Brain, Disease Models, Animal, Dopamine, Humans, Nicotine, Receptors, Nicotinic, Reinforcement, Psychology, Substance Withdrawal Syndrome, Smoking Cessation

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.

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