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Cited by 173Nicotinic Acetylcholine Receptors StudyReceptor Mechanisms and SignalingNeurotransmitter Receptor Influence on Behavior

Nicotine Withdrawal

Open access
McLaughlin, Ian, Dani, John A., De Biasi, Mariella·2015·Current Topics in Behavioral Neurosciences
DOI 10.1007/978-3-319-13482-6_4PMC PMC4542051
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Abstract

An aversive abstinence syndrome manifests 4-24 h following cessation of chronic use of nicotine-containing products. Symptoms peak on approximately the 3rd day and taper off over the course of the following 3-4 weeks. While the severity of withdrawal symptoms is largely determined by how nicotine is consumed, certain short nucleotide polymorphisms (SNPs) have been shown to predispose individuals to consume larger amounts of nicotine more frequently--as well as to more severe symptoms of withdrawal when trying to quit. Additionally, rodent behavioral models and transgenic mouse models have revealed that specific nicotinic acetylcholine receptor (nAChR) subunits, cellular components, and neuronal circuits are critical to the expression of withdrawal symptoms. Consequently, by continuing to map neuronal circuits and nAChR subpopulations that underlie the nicotine withdrawal syndrome--and by continuing to enumerate genes that predispose carriers to nicotine addiction and exacerbated withdrawal symptoms--it will be possible to pursue personalized therapeutics that more effectively treat nicotine addiction.

Integrity signals

Registry

Crossref · 10.1007/978-3-319-13482-6_4

Cites

137 of 137 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

78 of 116 cited sources checked · 51 supported · 2 flagged · accuracy not yet measured

  • Interpretationcitation

    Because β2-to-β4 replacement increases nAChR levels at the plasma membrane without nicotine, nicotine's proposed chaperoning function may be less effective.

    “As replacement of β2 by β4 is sufficient to increase nAChR levels at the plasma membrane in the absence of nicotine, the proposed “chaperoning” function of nicotine might not be as effective (Srinivasan et al. 2011; Henderson et al. 2014).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Srinivasan et al. 2011 source

      The TIRF microscopy section reports 1.9-fold higher plasma-membrane receptor density with β4 than with β2, supporting the first part of the claim. The Discussion says nicotine produced only a small further increase for an enhanced-export β2 mutant designed to mimic features of β4, but the paper does not establish that nicotine chaperoning is less effective for receptors containing β4 itself. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Henderson et al. 2014 source

      The Results section on nicotine-induced up-regulation (page unavailable) reports a greater than threefold increase in plasma-membrane α6β4* receptors after nicotine treatment, while α6β2 receptors showed no increase at 50 nM. That is contrary to the suggested weaker nicotine effect with β4. The paper’s separate finding that β3 increases baseline membrane density does not establish the claimed effect of replacing β2 with β4. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Heritability accounts for 50-75% of the risk for nicotine dependence, depending on how dependence is defined and which population is studied.

    “Depending on the parameters used to define dependence, and the population considered, heritability contributes 50–75 % of the risk for dependence (Dokal et al. 1989; Hall et al. 2002; Lessov et al. 2004; Furberg et al. 2010; Nugent et al. 2014; also see chapters entitled Genetics of Smoking Behaviour and Pharmacogenetics of Nicotine and Associated Smoking Behaviors; volume 23).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Dokal et al. 1989 source
    • cites Hall et al. 2002 source

      The Twin studies section says genetic influences play an important role in nicotine dependence, and the Conclusions say dependence is partially under genetic control. But the copy does not give a 50–75% heritability estimate for nicotine dependence; its numerical heritability ranges in Twin studies concern smoking initiation, a different outcome. Pages are not available in the indexed passages. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Lessov et al. 2004 source
  • Premisecitation

    α6* nAChRs have a documented role in withdrawal-induced conditioned place aversion.

    “and there is a documented role for α6* nAChRs in withdrawal-induced CPA (Jackson et al. 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Jackson et al. 2009 source
  • Premisecitation

    Sequence variants linked to smoking behavior are located in regions containing the CHRNB3-CHRNA6 genes on chromosome 8p11.

    “While sequence variants associated with smoking behavior lie within the regions that harbor the CHRNB3-CHRNA6 genes on chromosome 8p11 (Thorgeirsson et al. 2010)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Thorgeirsson et al. 2010 source
  • Interpretationcitation

    Lack of α7 delays withdrawal symptoms rather than eliminating them.

    “When the anhedonic affective state was evaluated between 8 and 100 h after nicotine withdrawal, ICSS thresholds were equally elevated in α7 WT and null littermates, indicating that a lack of α7 nAChR subunits delays, rather than abolishes, withdrawal symptoms.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Stoker et al. 2012 source
  • May combine two claims. 34
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Premisecitation

    α5 knockout mice show neither physical signs of spontaneous or mecamylamine-precipitated nicotine withdrawal nor withdrawal-induced hyperalgesia.

    “α5 KO mice do not display physical symptoms associated with both spontaneous and mecamylamine-precipitated nicotine withdrawal (Salas et al. 2009) nor withdrawal-induced hyperalgesia (Jackson et al. 2008).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Salas et al. 2009 source
    • cites Jackson et al. 2008 source

      Jackson et al.’s Results (‘Role of the α5 nAChR Subunit in Precipitated Nicotine Withdrawal’) report significant withdrawal-induced hyperalgesia in α5 knockout mice, contrary to the part of the sentence cited to Jackson et al. The statement about spontaneous and mecamylamine-precipitated physical symptoms is cited to Salas et al. (2009), not to this source. (LLM, conf=0.95)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    DSM-5 lists seven primary symptoms of nicotine withdrawal: irritability/anger/frustration, anxiety, depressed mood, difficulty concentrating, increased appetite, insomnia, and restlessness.

    “The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) reports 7 primary symptoms associated with nicotine withdrawal: irritability/anger/frustration, anxiety, depressed mood, difficulty concentrating, increased appetite, insomnia, and restlessness (American Psychiatric Association 2013).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites American Psychiatric Association 2013 source

      The indexed passages under “Symptoms and patterns” (11 September 2026; no page given) describe depressive episodes, not nicotine withdrawal. Searches for the seven listed symptoms and for tobacco-withdrawal diagnostic symptoms found no passage that verifies the DSM-5 list or its count. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Genetic factors may explain 29-53% of the variance in withdrawal symptoms and about half of the variance in quitting success.

    “Genetic factors may also account for 29–53 % of the variance in withdrawal symptoms and approximately 50 % of the variance in quitting success (Xian et al. 2003, 2005; Pergadia et al. 2006).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Xian et al. 2003 source
    • cites Xian et al. 2005 source
    • cites Pergadia et al. 2006 source

      The Abstract reports 29% and 53% heritability for depressed mood during withdrawal in women and men, respectively, but gives 26–43% for most other symptoms and 9% for decreased heart rate. The paper does not report that genetic factors explain approximately 50% of variance in quitting success; its Introduction discusses cessation failure without that estimate. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    α2 knockout mice show more somatic withdrawal symptoms in novel environments but no somatic withdrawal signs in habituated environments.

    “α2 KO mice exhibit more somatic symptoms of withdrawal in novel environments (Lotfipour et al. 2013), but display no somatic signs of withdrawal in habituated environments (i.e., the home cage) (Salas et al. 2009).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Lotfipour et al. 2013 source
    • cites Salas et al. 2009 source

  • May combine two claims.

    Premisecitation

    β4 knockout mice show no somatic signs of nicotine withdrawal or hyperalgesia after mecamylamine-precipitated withdrawal.

    “β4 KO mice exhibit no somatic signs of nicotine withdrawal or hyperalgesia following mecamylamine-induced withdrawal (Salas et al. 2004).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Salas et al. 2004 source

      The Results section reports fewer somatic signs in nicotine-treated β4 knockout mice after mecamylamine, not no signs. It also reports no hyperalgesia in β4 knockout mice, but the Animals section specifies that the hyperalgesia tests were performed after interruption of nicotine infusion, rather than after mecamylamine-precipitated withdrawal. Page numbers are not provided in the supplied copy. (LLM, conf=0.94)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Locomotor activity and prepulse inhibition of acoustic startle are controlled at least partly by nigrostriatal and mesolimbic dopaminergic activity.

    “behaviors that are controlled, at least in part, by nigrostriatal and mesolimbic dopaminergic activity (Cui et al. 2003)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Cui et al. 2003 source

  • May combine two claims.

    Premisecitation

    β2 knockout mice have somatic withdrawal signs and abstinence-induced hyperalgesia comparable to wild-type mice.

    “β2 KO mice exhibit levels of somatic signs of withdrawal and abstinence-induced hyperalgesia comparable to those of WT mice (Salas et al. 2004).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Salas et al. 2004 source

      The Results section reports that β2 knockout mice had somatic withdrawal scores similar to nicotine-treated controls after mecamylamine injection. Its hyperalgesia results compare wild-type mice with β4 knockout mice, not β2 knockout mice, so the claimed comparison of abstinence-induced hyperalgesia is not supported (page not specified in our copy). (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    α3β4* nAChRs are the most likely contributors to physical components of nicotine withdrawal, given high α3 and β4 mRNA expression in the MHb and the ability of α-conotoxin AuIB to block somatic withdrawal signs.

    “α3β4* nAChRs are the most likely contributors to physical components of withdrawal given the high levels of expression of α3 and β4 mRNA in the MHb, and the fact that the α3β4-selective α-conotoxin AuIB blocks the emergence of somatic signs of withdrawal (Jackson et al. 2013).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Jackson et al. 2013 source

      The Results (section 3.4; page unavailable) report that AuIB dose-dependently reduced somatic signs of nicotine withdrawal, and the Discussion (section 4; page unavailable) links α3β4* receptors to physical withdrawal and notes high α3 and β4 subunit expression in the MHb. The copy does not specify that this expression is mRNA expression, and it says α5 receptors also mediate somatic signs; it therefore does not establish α3β4* receptors as the most likely contributors relative to other receptors. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    β3 knockout mice have altered hypothalamic-pituitary-adrenal axis responses, as also reported for α5 knockout mice.

    “As reported for the α5 KO mice (Gangitano et al. 2009), β3 KO mice have altered hypothalamic pituitary adrenal axis responses (Booker et al. 2007).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Gangitano et al. 2009 source
    • cites Booker et al. 2007 source

  • May combine two claims.

    Premisecitation

    β3 knockout mice show changes in locomotor activity and prepulse inhibition of acoustic startle.

    “Changes were also reported for locomotor activity and prepulse inhibition of acoustic startle”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Cui et al. 2003 source

  • May combine two claims.

    Premisecitation

    Varenicline, an FDA-approved smoking cessation drug, acts as a partial agonist at α6β2* nAChRs.

    “a non-nicotine pharmaceutical currently FDA approved for the treatment of smoking cessation, varenicline, acts as a partial agonist at α6β2* nAChRs (Grady et al. 2010; Bordia et al. 2012).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Grady et al. 2010 source
    • cites Bordia et al. 2012 source

  • May combine two claims.

    Premisecitation

    α6 nAChR subunits have a selective role in the affective manifestations of withdrawal and do not influence somatic withdrawal symptoms.

    “There was no influence on the somatic symptoms of withdrawal, suggesting a selective role for α6 nAChR subunits in the affective manifestations of withdrawal (Jackson et al. 2009).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Jackson et al. 2009 source

  • May combine two claims.

    Premisecitation

    The dopaminergic VTA is implicated in rewarding aspects of addictive drugs and also participates in signaling aversion and lack of expected reward.

    “While the DAergic VTA has been widely implicated in the rewarding aspects of addictive drugs, it has also been shown to participate in the signaling of aversion and lack of expected reward (Schultz et al. 1998; Ungless et al. 2004; Tobler et al. 2007; De Biasi and Dani 2011).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Schultz et al. 1998 source
    • cites Ungless et al. 2004 source
    • cites Tobler et al. 2007 source

      The Discussion (page unavailable) says dopamine-neuron responses are stronger for cues predicting greater reward, supporting a general role in reward signaling. It does not establish that the VTA signals aversion or the absence of an expected reward, or address the rewarding effects of addictive drugs. (LLM, conf=0.81)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Receptor desensitization may be a major contributor to upregulation in chronic users of nicotine-containing products.

    “It has been suggested that receptor desensitization may be a major contributor to the upregulation observed in chronic users of nicotine-containing products (Benowitz 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Benowitz 2008 source

  • May combine two claims.

    Premisecitation

    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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gould et al. 2012 source

      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

  • May combine two claims.

    Interpretationcitation

    The effect of nicotine on contextual fear conditioning during withdrawal is not simply due to a lowered threshold of fear responses, because cued fear conditioning was equivalent between nicotine-treated and nicotine-naïve groups.

    “This effect was not attributable simply to a lowered threshold of fear responses inherent to the effects of nicotine because cued FC was equivalent between nicotine-treated and nicotine-naïve groups.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Davis et al. 2005 source

  • May combine two claims.

    Premisecitation

    Nicotine withdrawal increases CRF in the CeA, and blockade of CRF1 receptors reduces nicotine withdrawal-induced anxiety-like behavior.

    “Nicotine withdrawal leads to an increase in CRF in the CeA, and blockade of CRF1 receptors diminishes nicotine withdrawalinduced anxiety-like behavior (George et al. 2007).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites George et al. 2007 source

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

    Premisecitation

    The MHb also expresses norepinephrine, serotonin, ATP, and several neuropeptides.

    “The MHb also hosts the expression of norepinephrine (NE), serotonin, ATP, and several neuropeptides (Dao et al. 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Dao et al. 2014 source

  • May combine two claims.

    Premisecitation

    The LHb sends excitatory glutamatergic projections to the RMTg and is a major component of the circuit underlying negative reward.

    “The LHb sends excitatory glutamatergic projections to the RMTg and is a major component of the circuit underlying negative reward (Dani and De Biasi 2013).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Dani and De Biasi 2013 source

  • May combine two claims.

    Premisecitation

    Infusion of an α3β4* nAChR-selective antagonist into the IPN elicits somatic withdrawal signs in nicotine-naïve mice and more total symptoms in chronically nicotine-treated mice.

    “Additionally, infusion of an α3β4* nAChR-selective antagonist into the IPN elicited somatic withdrawal signs in nicotine-naïve mice and an even greater number of total symptoms in mice chronically treated with nicotine (Zhao-Shea et al. 2013).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Zhao-Shea et al. 2013 source

  • May combine two claims.

    Premisecitation

    RMTg activity increases with aversive stimuli and decreases with reward stimuli, showing inversely correlated signaling patterns.

    “Activity in the RMTg increases upon exposure to aversive stimuli and decreases upon exposure to reward stimuli, representing inversely correlated signaling patterns (Hong et al. 2011).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hong et al. 2011 source

      The Results (‘Reward-related properties of primate RMTg neurons’; page not provided) report that reward-negative neurons increased activity when an expected reward was absent and decreased activity when an unexpected reward occurred. The paper also reports reward-positive neurons with the opposite pattern. It supports inverse responses to reward versus non-reward in a subset of RMTg neurons, but does not establish the claimed response to aversive stimuli generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The habenular complex comprises lateral and medial habenular nuclei and is a diencephalic epithalamic structure located ventrally along the dorsal third ventricle.

    “The habenular complex, comprising the lateral (LHb) and medial (MHb) nuclei, is a diencephalic, epithalamic structure located ventrally along the dorsal third ventricle (Dani and De Biasi 2013).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Dani and De Biasi 2013 source

      The Dopamine Systems section says the lateral and medial habenula form the habenula complex, an epithalamic structure by the third ventricle. It does not specify that the complex lies ventrally along the dorsal third ventricle; that more precise location is unsupported by this passage. No page number is provided in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationreasoning

    Multiple genetic loci influence how severe withdrawal symptoms are and whether a person can abstain from smoking.

    “Currently, the literature suggests that multiple genetic loci influence the severity of withdrawal symptoms and the ability to abstain from smoking.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A transgenic mouse overexpressing β4 nAChR subunits shows altered nicotine consumption and conditioned place aversion.

    “Indeed, a transgenic mouse model that overexpresses β4 nAChR subunits exhibits altered nicotine consumption and CPA (Frahm et al. 2011)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Frahm et al. 2011 source

  • May combine two claims.

    Premisecitation

    The MHb/IPN pathway is crucial for the physical signs of nicotine withdrawal and is the likely site where α5-containing nAChRs act on this phenotype.

    “The MHb/IPN pathway plays a crucial role in mediating the physical manifestations of nicotine withdrawal and is the likely location of the effects of α5-containing nAChR on this phenotype (Salas et al. 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Salas et al. 2009 source

  • May combine two claims.

    Interpretationreasoning

    Because AuIB does not affect affective withdrawal symptoms in EPM and CPA paradigms, α6β4* nAChRs might be involved.

    “Because AuIB does not interfere with the affective symptomatology of withdrawal in the EPM and CPA paradigms, α6β4* nAChRs might be involved.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The mouse withdrawal syndrome can be relieved by nicotine or by human cessation aids such as bupropion or varenicline.

    “The withdrawal syndrome exhibited can be alleviated by nicotine administration—akin to nicotine replacement strategies such as nicotine patches or gum—or by administration of pharmacological agents used as cessation aids in humans, such as bupropion or varenicline (Rennard and Daughton 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rennard and Daughton 2014 source

  • May combine two claims.

    Interpretationcitation

    β2 nAChR subunits participate in the signaling responsible for affective but not somatic symptoms of nicotine withdrawal.

    “Overall, these results suggest participation of β2 nAChR subunits in the signaling responsible for affective, but not somatic, symptoms of nicotine withdrawal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Co-expression of β3 increases α6β2 and α6β4 receptor levels and enhances nicotine-induced upregulation of α6β2β3 receptors compared with α6β2 receptors.

    “Conversely, co-expression of β3 increases α6β2 and α6β4 receptor levels and enhances nicotine-induced upregulation of α6β2β3 receptors compared to α6β2 receptors (Tumkosit et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tumkosit et al. 2006 source

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

    Premisereasoning

    Several brain structures have already been implicated in the nicotine withdrawal syndrome.

    “Thus far, several brain structures have been already implicated in the withdrawal syndrome.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Different anatomical structures in the CNS express distinct populations of nAChRs.

    “Different anatomical structures in the CNS express distinct populations of nAChRs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because desensitization and recovery from upregulation during withdrawal have incongruent rates, a state is established with more receptors than in nicotine-naïve individuals and these receptors are less responsive to agonist.

    “Accordingly, as the rates of desensitization and recovery from receptor upregulation during nicotine withdrawal are incongruent, a physiological landscape is established in which there are more receptors expressed than would be present in nicotine-naïve individuals, and these receptors are less responsive to agonist binding.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The mesocorticolimbic dopamine system is critical to the development of addictive behaviors, and dopamine signaling is involved in reward-based reinforcement of drug-derived behaviors.

    “The mesocorticolimbic dopamine (DA) system has been identified as critical to the development of addictive behaviors, and DA signaling is involved in reward-based reinforcement of drug-derived behaviors.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Candidate SNPs can have many biochemical functions, such as altering DNA methylation, histone modification, or DNA accessibility to transcription factor binding, which can affect when, where, and how much a gene and its protein are expressed.

    “Candidate SNPs can have a multitude of biochemical functions, such as altering DNA methylation, histone modification, or accessibility of DNA to transcription factor binding that can impact when, where, and how much a gene, and its protein, is expressed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The nicotine withdrawal syndrome is most severe in the first week but can persist longer.

    “The syndrome is most severe in the first week, but it can persist for longer periods of time.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Common variants explain only a small percentage of variance in smoking-related phenotypes, so increasing attention is being paid to functional analysis of rare variants.

    “Increasing attention is being paid to the functional analysis of rare variants, as common variants can explain only a small percentage of the variance in smoking-related phenotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mice chronically treated with nicotine show withdrawal symptoms after mecamylamine microinjection into the MHb and IPN, but not after injection into cortex, hippocampus, or VTA.

    “Mice chronically treated with nicotine exhibit symptoms of withdrawal upon microinjection of mecamylamine into the MHb and IPN, but fail to manifest withdrawal symptoms when mecamylamine is injected to the cortex, hippocampus, or VTA (Salas et al. 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Salas et al. 2009 source

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

    Premisecitation

    The habenula participates in signaling underlying fear, anxiety, depression, and stress.

    “The habenula has been demonstrated to participate in the signaling underlying fear, anxiety, depression, and stress (Viswanath et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Viswanath et al. 2013

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

  • May combine two claims.

    Premisenone given

    The extended amygdala is implicated in stress-related components of drug withdrawal and is a site of interaction between CRF and NE transmission.

    “The system has been implicated in stress-related components of drug withdrawal and is a site of interaction between corticotropinreleasing factor (CRF) and NE transmission.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The IPN is located in the ventral midbrain, with the VTA and median raphe nucleus located dorsally.

    “The IPN is located in the ventral midbrain, with the VTA and median raphe nucleus located dorsally.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Given the polygenic nature of nicotine addiction, many other mechanisms and brain areas likely influence withdrawal manifestations.

    “Given the polygenic nature of nicotine addiction, many other mechanisms and many other brain areas are likely to influence the manifestations of withdrawal.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Nicotine addiction is polygenic.

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

    Interpretationreasoning

    A collection of genes likely operates collectively to predispose or protect individuals to or from nicotine addiction and withdrawal.

    “More work is necessary at the bench and in the clinic, as a collection of genes likely operates collectively to predispose or protect individuals to or from nicotine addiction and withdrawal.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    During withdrawal, relapse is incentivized by nicotine's ability to alleviate or abolish withdrawal symptoms.

    “During this time, relapse is incentivized by the ability of nicotine to alleviate or abolish withdrawal symptoms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Genetic studies of nicotine dependence and smoking cessation have identified several risk factors using GWAS, candidate gene approaches, and pharmacogenetic analyses.

    “Genetic studies of nicotine dependence and smoking cessation have identified several risk factors using GWAS, candidate gene approaches, and pharmacogenetic analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    For many SNPs, there is no change in protein sequence, making it harder to formulate clear functional hypotheses.

    “For many of the SNPs, however, there is no change in protein sequence, and therefore, it is harder to formulate clear functional hypothesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cognitive deficits manifest during nicotine withdrawal, including difficulty concentrating, increased reaction times in sustained attention tasks, and impaired episodic and working memory.

    “In addition, there are cognitive deficits that manifest during nicotine withdrawal, including difficulty concentrating, increased reaction times in tasks requiring sustained attention, and impaired episodic and working memory (Myers et al. 2008; Wesnes et al. 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Myers et al. 2008 source
    • cites Wesnes et al. 2013 source
46 of 46

  • The paper relies on this without support.

    Nicotine withdrawal begins 4–24 hours after stopping chronic nicotine product use, peaks around the third day, and then declines over the following 3–4 weeks.

    “An aversive abstinence syndrome manifests 4–24 h following cessation of chronic use of nicotine-containing products. Symptoms peak on approximately the 3rd day and taper off over the course of the following 3–4 weeks.”

  • The paper relies on this without support.

    How nicotine is consumed is the main determinant of how severe withdrawal symptoms will be.

    “While the severity of withdrawal symptoms is largely determined by how nicotine is consumed”

  • The paper relies on this without support.

    No preclinical data exist on how the β3 null mutation affects nicotine-related behavior.

    “no preclinical data are available on the effects of the β3 null mutation on nicotine-related behavior.”

  • The paper relies on this without support.

    Nicotine addiction is polygenic.

    “Given the polygenic nature of nicotine addiction”
4 of 4

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3 of the 140 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Graham AW, Schultz TK, Mayo-Smith MF, Ries RK, Wilford B (2007) Principles of addiction medicine. Lippincott Williams & Wilkins, Philadelphia

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Related

Authors
McLaughlin, I., Dani, J. A., & De Biasi, M.
Affiliations
University of Pennsylvania (US)
ORCID
Dani, John A.
Venue
Current Topics in Behavioral Neurosciences
Publisher
Springer International Publishing
Published
2015
Volume
24
Pages
99-123
ISSN
  • 1866-3370 (ISSN-L)
  • 1866-3389
DOI
10.1007/978-3-319-13482-6_4
PMC
PMC4542051
OpenAlex
W4211219695
Cited by
173
References
140
Citations by year
2026: 16 · 2025: 28 · 2024: 21 · 2023: 30 · 2022: 13 · 2021: 17 · 2020: 21 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 3 · 2015: 2
FWCI
10.04
Type
book chapter
Language
en
Open access
Licence
Locations
  • Current topics in behavioral neurosciences (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
nicotine withdrawal, nicotine dependence, single nucleotide polymorphisms, nicotinic acetylcholine receptors, nAChR subunits, neural circuits, transgenic mouse model, personalized treatment
MeSH terms
Animals, Brain, Humans, Nicotine, Receptors, Nicotinic, Substance Withdrawal Syndrome

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.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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

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

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