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Cited by 452Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationNeuroscience and Neuropharmacology Research

It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood

Open access
PICCIOTTO, M, ADDY, N, MINEUR, Y, BRUNZELL, D·2008·Progress in Neurobiology
DOI 10.1016/j.pneurobio.2007.12.005PMC PMC2390914
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Abstract

Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both these processes to nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with smoking behavior and activation and desensitization of nAChRs may contribute to both primary and conditioned drug reward. Similarly, studies of the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that nicotine’s behavioral effects in addiction and mood cannot be explained by either nAChR activation or desensitization alone; both processes contribute, often simultaneously across receptor subtypes and brain regions. It synthesizes electrophysiological, pharmacological, genetic, imaging, and behavioral evidence to propose that activation and desensitization jointly shape nicotine reward, conditioned reinforcement, and antidepressant-like effects.

Key findings

  • Both activation and desensitization of nicotinic acetylcholine receptors (nAChRs) contribute to nicotine-related behaviors, including primary reward, conditioned reinforcement, and affective modulation; the review concludes neither process alone is sufficient.
  • β2* nAChRs, especially α4/β2* subtypes, are critical for primary reinforcing effects of nicotine: β2* antagonists block nicotine self-administration, and β2* null mice lack nicotine self-administration, DA-dependent locomotor activation, nicotine-enhanced NAc DA release, and nicotine-associated enhancement of conditioned reinforcement.
  • Desensitization may enhance the salience of smoking-associated cues: low nicotine concentrations (20–80 nM) produced robust β2* desensitization without α7 desensitization, and desensitization of β2* nAChRs on GABA terminals in VTA can increase DA neuron activity and shift DA responses toward phasic firing.
  • Antidepressant-like effects of nicotinic agents may reflect a balance between activation and desensitization: nicotine, nicotinic partial agonists, and nicotinic antagonists can all show antidepressant-like effects, with evidence implicating α4/β2* and α7* nAChRs.
  • Human data cited include blood nicotine peaking at ∼50 ng/ml (300 nM) 5 minutes after one cigarette, chronic smoker levels of 10–50 ng/ml (60–300 nM), and PET β2* occupancy of ∼88% after one cigarette, corresponding to plasma levels linked to 50% desensitization of α4β2 nAChRs.

Methods

  • Narrative review of published literature on nAChR activation and desensitization in nicotine addiction and mood, integrating electrophysiological, neurochemical, pharmacological, knockout mouse, imaging, and behavioral studies.
  • Evidence discussed includes in vitro and brain-slice electrophysiology, cyclic voltammetry, microdialysis, PET/SPECT imaging in humans, self-administration and conditioned reinforcement paradigms in rodents, and forced swim/tail suspension/learned helplessness models.
  • The review synthesizes findings across receptor subtypes (notably α7*, β2*, α4/β2*, α6/β2*) and brain regions including VTA, nucleus accumbens, hippocampus, and amygdala.

Limitations

  • The paper states several unresolved issues: whether pre- and post-synaptic nAChR subtypes differ in desensitization susceptibility, whether nAChR upregulation increases functional activatable receptors or mainly desensitized receptors, and why α6/β2* upregulation findings are variable.
  • The paper notes that the PET ligand may only reveal the highest-affinity subclass of nAChRs, likely desensitized receptors, so activatable nAChRs may not be measured; it also notes that the amygdala link is correlative and requires further causal testing.
  • Evident from the text: this is a review, not a primary experimental study, so its conclusions depend on synthesis of heterogeneous animal, human, in vitro, and clinical findings; the paper also states there is no solid consensus on the neural substrates critical for mood disorders.

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

Integrity signals

Registry

Crossref · 10.1016/j.pneurobio.2007.12.005

Cites

172 of 172 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

23 of 116 cited sources checked · 12 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Steady states of nicotine that would be achieved in the bloodstream of a regular smoker can desensitize midbrain nAChRs with a time course of recovery that requires several minutes.

    “In addition, electrophysiological studies show that steady states of nicotine that would be achieved in the bloodstream of a regular smoker can desensitize midbrain nAChRs with a time course of recovery that requires several minutes (Pidoplichko et al., 1997; Wooltorton et al., 2003).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Pidoplichko et al., 1997 source
    • cites Wooltorton et al., 2003 source

      The section on nicotine concentrations obtained from tobacco reports that smoker-relevant concentrations (20–80 nM) desensitized the slower nAChR current in VTA neurons. The discussion says recovery can be slow and variable, but our copy does not establish that recovery from this desensitization requires several minutes; it also notes that some receptor subtypes remain functional at these concentrations. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Acute activation of nAChRs by nicotine can stimulate the firing of DA neurons.

    “As noted in Section 1, it is clear that acute activation of nAChRs by nicotine can stimulate the firing of DA neurons (Grenhoff et al., 1986; Klink et al., 2001; Picciotto et al., 1998; Svensson et al., 1990).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Grenhoff et al., 1986 source
    • cites Klink et al., 2001 source
    • cites Picciotto et al., 1998 source
  • Premisecitation

    Increased surface expression of nAChRs following chronic nicotine can indeed result in increased activation of nAChRs.

    “It appears that the increased surface expression of nAChRs following chronic nicotine can indeed result in increased activation of nAChRs (Vallejo et al., 2005; Wonnacott, 1990), although the discrepancy between studies suggests that there is a dynamic equilibrium between activation and desensitization of nAChRs following chronic nicotine exposure.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Vallejo et al., 2005 source

      The Introduction reports increased receptor responses after long-term nicotine exposure, but explicitly concludes that upregulation is not caused by an increase in the number of surface receptors. The Discussion likewise describes a functional change in existing α4β2 receptors. Thus the increased activation is supported, but attributing it to increased surface expression is not. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites Wonnacott, 1990 source
  • Premisecitation

    At even lower nicotine concentrations (20-80 nM), robust β2* desensitization is observed without any α7 desensitization.

    “Furthermore, when even lower nicotine concentrations (20-80 nM) were examined in an attempt to model the low levels experienced by chronic smokers over long time periods, robust β2* desensitization was observed without any α7 desensitization (Wooltorton et al., 2003).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Wooltorton et al., 2003 source
  • Premisecitation

    Desensitized nAChRs have a higher affinity for ACh and other ligands than those in the activatable state.

    “Despite the decreased response of AChRs to agonists in the desensitized state, desensitized nAChRs have a higher affinity for ACh and other ligands than those in the “activatable” state (Heidmann et al., 1983; Quick and Lester, 2002);”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Heidmann et al., 1983 source
    • cites Quick and Lester, 2002 source
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Interpretationcitation

    Studies in β2 KO mice show that both functional deletion and nicotine administration in wild-type mice can lead to the same cellular or behavioral effects, suggesting that nicotine administration may normally desensitize β2* nAChRs in these paradigms and that desensitization then contributes to these cellular or behavioral responses.

    “A number of studies in knockout (KO) mice lacking the β2 subunit of the nAChR have shown that both functional deletion in KO mice and nicotine administration in wild-type mice can lead to the same cellular or behavioral effects, suggesting that nicotine administration may normally desensitize β2* nAChRs in these paradigms and that desensitization then contributes to these cellular or behavioral”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Brunzell et al., 2006 source
    • cites Cohen et al., 2005 source
    • cites Mechawar et al., 2004 source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a PET imaging study, β2* occupancy was ∼88% after just 1 cigarette, with corresponding plasma levels that have been shown to lead to 50% desensitization of α4β2 nAChRs.

    “In a recent positron emission tomography (PET) imaging study, β2* occupancy was ∼ 88% percent after just 1 cigarette, with corresponding plasma levels that have been shown to lead to 50% desensitization of α4β2 nAChRs (Brody et al., 2006).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Brody et al., 2006 source

      The Results (Table 2; page unavailable) report 88% receptor occupancy 3.1 hours after one cigarette, with a corresponding venous plasma nicotine level of 3.8 ng/mL. The Comment (page unavailable) says a lower concentration, 0.87 ng/mL, is in the range associated with 50% desensitization; it does not establish that the level measured after one cigarette leads to exactly 50% desensitization. The PET study measured occupancy, not desensitization. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Nicotine-mediated neurotransmitter release can occur after acute nicotine exposure that activates nAChRs and after chronic nicotine exposure that desensitizes nAChRs.

    “For instance, nicotine-mediated neurotransmitter release can occur after acute nicotine exposure that activates nAChRs and after chronic nicotine exposure that desensitizes nAChRs (Benwell and Balfour, 1992; Iyaniwura et al., 2001).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Benwell and Balfour, 1992 source

      The Results and Discussion (pages not available in our copy) report increased nucleus accumbens dopamine after repeated nicotine treatment and infer dopamine release after acute treatment, although the acute increase in extracellular dopamine was not statistically significant without an uptake inhibitor. They do not establish that acute exposure activates nAChRs or that chronic exposure desensitizes them; those receptor mechanisms are not supported by this paper. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Iyaniwura et al., 2001 source

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

    Interpretationcitation

    Maintained nAChR desensitization may be important for relieving nicotine withdrawal in human smokers.

    “For instance, it has been suggested that maintained nAChR desensitization may be important for relieving nicotine withdrawal in human smokers (Brody et al., 2006) as is discussed below.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Brody et al., 2006 source
    • Rests on an assumption: The behavioral and neurochemical effects of nicotine in rodent models are relevant to human tobacco smoking and nicotine addiction.

  • May combine two claims.

    Premisecitation

    Repeated nicotine administration leads to increased release of dopamine that persists and shows a sensitized response despite nAChR desensitization.

    “As mentioned earlier, repeated nicotine administration leads to increased release of dopamine that persists, and indeed shows a sensitized response (increased dopamine (DA) release in response to challenge with the same nicotine dose), despite any nAChR desensitization that is likely to have occurred (Benwell and Balfour, 1992; Iyaniwura et al., 2001).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Benwell and Balfour, 1992 source

      The Results (‘The effect of acute and subchronic nicotine’; page unavailable) report elevated basal nucleus accumbens dopamine 27 hours after the last nicotine injection, and the Discussion reports an enhanced dopamine response to a nicotine challenge after pretreatment. The Discussion concludes that the dopamine system may become sensitized. Our copy does not establish that nAChRs had desensitized, so the ‘despite desensitization’ part is unsupported by this paper. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Iyaniwura et al., 2001 source

  • May combine two claims.

    Premisecitation

    Presynaptic effects of lower concentrations of nicotine blocked by α7* selective agents persist in the continued presence of nicotine in rat and mouse brain slices, whereas presynaptic effects blocked by β2* selective agents desensitize during continued nicotine application.

    “More recent studies have shown that presynaptic effects of lower concentrations of nicotine that are blocked by nicotinic agents that are thought to be selective for α7* nAChRs persist in the continued presence of nicotine in rat (Mansvelder et al., 2002) and mouse (Wooltorton et al., 2003) brain slices, whereas presynaptic effects that are blocked with agents thought to be selective for β2* nAChR”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Mansvelder et al., 2002 source
    • cites Wooltorton et al., 2003 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Mansvelder and McGehee, 2000 source

  • May combine two claims.

    Interpretationreasoning

    Chronic nicotine exposure would greatly increase response to environmental stimuli that increase DA neuron burst firing, and greatly decrease DA responses under conditions when these neurons were firing tonically.

    “Since sustained nicotine exposure shifts the balance toward glutamate-mediated excitation of DA neurons (Mansvelder et al., 2002; Wooltorton et al., 2003) the combination of increased drive on the cell bodies in the VTA and increased filtering in the striatum/nucleus accumbens suggests that chronic nicotine exposure would greatly increase response to environmental stimuli that increase DA neuron”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Mansvelder et al., 2002 source
    • cites Wooltorton et al., 2003 source
    • cites Rice and Cragg, 2004 source

  • May combine two claims.

    Premisecitation

    Bupropion is prescribed as both an antidepressant and as an aid to smoking cessation.

    “The most striking connection between smoking and depression is the norepinephrine-dopamine reuptake inhibitor bupropion, which is prescribed as both an antidepressant and as an aid to smoking cessation (Dwoskin et al., 2006; Hayford et al., 1999).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Dwoskin et al., 2006 source
    • cites Hayford et al., 1999 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The increased depressive symptoms following acute smoking cessation might be explained by clearance of nicotine coupled with persistent nAChR upregulation, resulting in increased ability of ACh to activate upregulated nAChRs.

    “this hypothesis suggests that the increased depressive symptoms observed in some patients following acute cessation from smoking might be explained by the fact that the clearance of nicotine following smoking cessation coupled with persistent nAChR upregulation (Staley et al., 2006) results in increased ability of ACh to activate these upregulated nAChRs.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Staley et al., 2006 source

  • May combine two claims.

    Premisecitation

    Cytisine blocks α4/β2* nAChRs but activates α3/β4* and α7* nAChRs.

    “cytisine, a nicotinic partial agonist that blocks α4/β2* nAChRs but activates α3/β4* and α7* nAChRs (Papke and Porter Papke, 2002; Picciotto et al., 1995)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Papke and Porter Papke, 2002 source

      The results section reports that cytisine activates human and rat α7 receptors, with lower efficacy in rat α7 receptors. The paper does not establish the claimed blockade of α4/β2* receptors or activation of α3/β4* receptors; its Introduction identifies GTS-21, not cytisine, as a partial agonist. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Picciotto et al., 1995 source

  • May combine two claims.

    Premisecitation
    § Abstract

    Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs).

    “Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs).”
    • Also stated in: § 1.2 Functional properties of nAChRs · plain
      “A fundamental property of nAChRs is their susceptibility to desensitization and inactivation following, and indeed in some cases independent of, channel opening (Giniatullin et al., 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Giniatullin et al., 2005 source

  • May combine two claims.

    Premisecitation

    β2* nAChRs have the highest affinity for nicotine and other agonists, while α7* nAChRs have a lower affinity for nicotine in vitro.

    “The β2* nAChRs are thought to have the highest affinity for nicotine and other agonists (Lippiello et al., 1987; McGehee and Role, 1995; Picciotto et al., 1995) while α7* nAChRs are thought to have a lower affinity for nicotine in vitro (Papke and Thinschmidt, 1998; Wonnacott, 1986).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Lippiello et al., 1987 source
    • cites McGehee and Role, 1995 source
    • cites Picciotto et al., 1995 source

  • May combine two claims.

    Interpretationcitation
    § Abstract

    Both nAChR activation and desensitization contribute to the effects of nicotine in the brain.

    “Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both of these processes to nicotine-mediated behaviors.”
    • Also stated in: § 1.1 Introduction · hedged
      “Emerging evidence for electrophysiological consequences of both nAChR activation and desensitization has provided mechanisms that are consistent with the contribution of both of these processes to nicotine-mediated behaviors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    There are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and both processes are important in the behavioral consequences of nicotine in tobacco smoking.

    “We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The behavioral and neurochemical effects of nicotine in rodent models are relevant to human tobacco smoking and nicotine addiction.

  • May combine two claims.

    Interpretationreasoning

    Despite compelling evidence that chronic nicotine exposure in human smokers results in profound nAChR desensitization, not all nAChRs are desensitized under these conditions.

    “Despite compelling evidence that chronic nicotine exposure, for example in human smokers, results in profound nAChR desensitization, examination of the different rates of activation and desensitization between α7 and β2* nAChRs suggests that not all nAChRs are desensitized under these conditions.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The behavioral and neurochemical effects of nicotine in rodent models are relevant to human tobacco smoking and nicotine addiction.

  • May combine two claims.

    Interpretationreasoning

    Both chronic nicotine administration and early withdrawal are sufficient to drive nAChR up-regulation.

    “Thus, it appears that both chronic nicotine administration and early withdrawal are sufficient to drive nAChR up-regulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Low level nicotine concentrations experienced by smokers over long periods preferentially desensitize α4β2 nAChRs on GABAergic terminals and not α7 nAChRs on glutamatergic terminals in the VTA, shifting presynaptic effects of nicotine from mixed inhibition and excitation of DA neurons toward the glutamatergic response.

    “The low level nicotine concentrations experienced by smokers over long periods are suggested to preferentially desensitize α4β2 nAChRs on GABAergic terminals and not α7 nAChRs on glutamatergic terminals in the VTA, thus shifting the presynaptic effects of nicotine from a mixed inhibition and excitation of DA neurons, toward the glutamatergic response to nicotine (Mansvelder et al., 2002; Mansvel”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Mansvelder et al., 2002 source
    • cites Mansvelder and McGehee, 2000 source

  • May combine two claims.

    Premisecitation

    At nicotine concentrations of 500 nM or higher, α7* nAChR activation is characterized by fast currents that desensitize on a millisecond timescale while β2* nAChRs desensitize more slowly on a second timescale.

    “As mentioned earlier, at nicotine concentrations of 500 nM or higher, electrophysiological studies in combination with pharmacological agents to isolate individual nAChR-mediated currents have shown that α7* nAChR activation is characterized by fast currents that desensitize on a millisecond timescale while β2* nAChRs desensitize more slowly on a second timescale (Couturier et al., 1990a; Giniat”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Couturier et al., 1990a

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

    • cites Giniatullin et al., 2005 source
    • cites Pidoplichko et al., 1997 source

  • May combine two claims.

    Interpretationreasoning

    Chronic nicotine exposure results in both peaks of activation and long-term desensitization of nAChRs.

    “The likelihood that chronic nicotine exposure results in both peaks of activation and long-term desensitization of nAChRs suggests that functional responses associated with chronic nicotine exposure due to smoking are due, at least in part, to nAChR desensitization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    This PET ligand may only reveal the highest affinity subclass of nAChRs, which are likely to be in the desensitized state; thus nAChRs in the activatable state may not be measured using this technique.

    “It should be noted, however, that this PET ligand may only reveal the highest affinity subclass of nAChRs, which are likely to be in the desensitized state (Changeux et al., 1984). Thus, nAChRs in the activatable state may not be measured using this technique.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Changeux et al., 1984 source

  • May combine two claims.

    Premisecitation

    β2* nAChRs are necessary for nicotine self-administration, DA-dependent locomotor activation, nicotine-associated enhancement of NAc DA release, and nicotine-associated enhancement of conditioned reinforcement.

    “Studies in β2* nAChR null mutant mice further show that β2* nAChRs are necessary for nicotine self-administration, DA-dependent locomotor activation, nicotine-associated enhancement of NAc DA release, and nicotine-associated enhancement of conditioned reinforcement (Brunzell et al., 2006; King et al., 2004; Marubio et al., 2003; Picciotto et al., 1998).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brunzell et al., 2006 source
    • cites King et al., 2004 source
    • cites Marubio et al., 2003 source

  • May combine two claims.

    Premisecitation

    Mecamylamine and the nicotine patch decrease symptoms of depression in depressed non-smoking patients and patients with Tourette's syndrome.

    “the non-competitive, non-selective nAChR antagonist mecamylamine as well as the nicotine patch, decrease symptoms of depression in depressed non-smoking patients and patients with Tourette's syndrome (Dursun and Kutcher, 1999; Mihailescu and Drucker-Colin, 2000; Salin-Pascual et al., 1995; Salin-Pascual et al., 1996).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dursun and Kutcher, 1999 source
    • cites Mihailescu and Drucker-Colin, 2000 source
    • cites Salin-Pascual et al., 1995 source

  • May combine two claims.

    Premisecitation

    Physostigmine can exacerbate mood disorders, with non-depressed subjects showing heightened anxiety, aggression and irritability, and depressed patients exhibiting prolonged and more severe symptoms.

    “Following treatment with physostigmine, non-depressed subjects had heightened anxiety, aggression and irritability, whereas depressed patients exhibited prolonged and more severe symptoms (Janowsky et al., 1974) and a majority of bipolar patients exhibited signs of depression (Oppenheim et al., 1979).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Janowsky et al., 1974 source
    • cites Oppenheim et al., 1979 source

  • May combine two claims.

    Premisecitation

    Genetic studies emphasize that depression and smoking can have similar genetic susceptibility but no causal connections exist between these two phenotypes.

    “genetic studies also emphasized that both can also have similar genetic susceptibility but that no causal connections exist between these two phenotypes (Kendler et al., 1993; McCaffery et al., 2003).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kendler et al., 1993 source
    • cites McCaffery et al., 2003 source

  • May combine two claims.

    Premisecitation

    Depressed patients have increased central concentrations of choline, which is reversed after recovery.

    “imaging studies have demonstrated that depressed patients have increased central concentrations of choline (the limiting precursor of ACh) and this is reversed after recovery (Charles et al., 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Charles et al., 1994 source

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

    Premisecitation

    The cholinergic-adrenergic theory of depression postulates that over-activation of the cholinergic component leads to depression.

    “The cholinergic-adrenergic theory of depression postulates that a fine balance exists between cholinergic and noradrenergic systems, and that over-activation of the cholinergic component would lead to depression (Janowsky et al., 1972).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Janowsky et al., 1972 source

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

    Premisecitation

    Some depressed patients initiate smoking as an attempt to self-medicate depressive symptoms with nicotine.

    “it is believed that some depressed patients initiate smoking as an attempt to self medicate depressive symptoms with nicotine (Markou et al., 1998; Patton et al., 1998).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Markou et al., 1998 source
    • cites Patton et al., 1998 source

  • May combine two claims.

    Interpretationcitation

    Activation of β2* nAChRs on DA soma, and potentially activation of α7* nAChRs, may contribute to nicotine-associated elevations in cue responsivity.

    “These data suggest that activation of β2*nAChRs on DA soma, and potentially activation of α7* nAChRs, may contribute to nicotine-associated elevations in cue responsivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Several classes of nicotinic agonists have antidepressant actions in human studies and animal models, but several nicotinic antagonists have potent antidepressant effects.

    “several classes of nicotinic agonists have antidepressant actions in both human studies and animal models (Ferguson et al., 2000; Gatto et al., 2004) but several nicotinic antagonists have shown to have potent antidepressant effects (Ferguson et al., 2000; Shytle et al., 2002).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ferguson et al., 2000 source
    • cites Gatto et al., 2004 source
    • cites Shytle et al., 2002 source

  • May combine two claims.

    Premisecitation

    High doses of fluoxetine or other classes of antidepressants can increase smoking quit rates, and these effects are reversed once treatment is stopped.

    “high doses of fluoxetine or other classes of antidepressants can increase quit rates, and these effects are reversed once the treatment is stopped (Hall et al., 1998; Hughes et al., 2000; Kotlyar et al., 2001).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hall et al., 1998 source
    • cites Hughes et al., 2000

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

    • cites Kotlyar et al., 2001 source

  • May combine two claims.

    Interpretationreasoning

    nAChRs in both the activatable and the desensitized state might drive both primary and conditioned reward associated with tobacco smoking.

    “This section will review the evidence suggesting that nAChRs in both the activatable and the desensitized state might drive both primary and conditioned reward associated with tobacco smoking.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The behavioral and neurochemical effects of nicotine in rodent models are relevant to human tobacco smoking and nicotine addiction.

  • May combine two claims.

    Premisecitation

    A subthreshold dose of mecamylamine combined with amitriptyline results in antidepressant-like effects in mice, reinforcing that blockade of nAChRs yields antidepressant-like effects.

    “a subthreshold dose of the nicotinic antagonist mecamylamine combined with the tricyclic antidepressant amitriptyline results in antidepressant-like effects in mice, reinforcing the idea that blockade of nAChRs yields antidepressant-like effects (Caldarone et al., 2004)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Caldarone et al., 2004 source
    • Rests on an assumption: Animal models of depression-like behavior (e.g., forced swim, learned helplessness, tail suspension) are valid predictors of human depression and antidepressant efficacy.

  • May combine two claims.

    Premisecitation

    Amitriptyline has no effect in neurochemical and behavioral assays of antidepressant efficacy in KO mice lacking the β2 nAChR subunit, suggesting that β2* nAChRs are involved in this antidepressant response.

    “the tricyclic antidepressant amitriptyline has no effect in neurochemical and behavioral assays of antidepressant efficacy in KO mice lacking the β2 nAChR subunit, strongly suggesting that β2* nAChRs are involved in this antidepressant response (Caldarone et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Caldarone et al., 2004 source
    • Rests on an assumption: Animal models of depression-like behavior (e.g., forced swim, learned helplessness, tail suspension) are valid predictors of human depression and antidepressant efficacy.
    • Rests on an assumption: nAChR subtypes and their functions are conserved between rodents and humans.

  • May combine two claims.

    Premisecitation
    § 4. Conclusions

    Varenicline is a partial agonist of α4/β2* nAChRs but also activates α7-type nAChRs.

    “Varenicline is a partial agonist of α4/β2* nAChRs (Coe et al., 2005), but also activates α7-type nAChRs (Mihalak et al., 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Coe et al., 2005 source
    • cites Mihalak et al., 2006 source

  • May combine two claims.

    Interpretationcitation
    § 4. Conclusions

    Nicotine patch or mecamylamine can significantly improve mood in patients affected by Tourette's syndrome, supporting that this effect of the patch is likely a result of nAChR desensitization.

    “The observation that nicotine patch or mecamylamine can significantly improve mood in patients affected by Tourette's syndrome (Silver et al., 2001) supports the idea that this effect of the patch is likely to be a result of nAChR desensitization.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Silver et al., 2001 source

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

    Interpretationnone given
    § 4. Conclusions

    Interference with cholinergic transmission ameliorates negative mood symptoms.

    “One potential reason for this possibility is that interference with cholinergic transmission ameliorates negative mood symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. Conclusions

    Neither nicotine patch nor varenicline are reinforcing.

    “neither patch (Jorenby et al., 1995) nor varenicline are reinforcing (Rollema et al., 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jorenby et al., 1995

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

    • cites Rollema et al., 2007 source

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

    Interpretationreasoning
    § 4. Conclusions

    This may be a widespread mechanism underlying the effects of nAChRs on a number of different brain systems.

    “This may be a widespread mechanism underlying the effects of nAChRs on a number of different brain systems.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given
    § 4. Conclusions

    Partial agonism or blockade of nAChRs may be helpful in decreasing cue-induced craving by decreasing the firing rate of VTA neurons, while maintaining the filtering effect on DA terminals that allows other salient reward signals to induce DA release in the NAc.

    “partial agonism or blockade of nAChRs may be helpful in decreasing cue-induced craving by decreasing the firing rate of VTA neurons, while maintaining the filtering effect on DA terminals that allows other salient reward signals to induce DA release in the NAc.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given
    § 4. Conclusions

    Both activation and desensitization appear to contribute to the primary rewarding properties of nicotine and to secondary conditioned reinforcement.

    “In summary, both activation and desensitization appear to contribute to the primary rewarding properties of nicotine and to secondary conditioned reinforcement.”
    Quote in the paperSubstantial claim
40 of 40

  • The paper relies on this without support.

    The behavioral and neurochemical effects of nicotine in rodent models are relevant to human tobacco smoking and nicotine addiction.

    “This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation.”

  • The paper relies on this without support.

    Animal models of depression-like behavior (e.g., forced swim, learned helplessness, tail suspension) are valid predictors of human depression and antidepressant efficacy.

    “Animal studies have also shown that chronic nicotine administration can elicit antidepressant-like effects in rats both in the learned helplessness (Semba et al., 1998) and the forced swim (Djuric et al., 1999; Tizabi et al., 1999) paradigms.”

  • The paper relies on this without support.

    nAChR subtypes and their functions are conserved between rodents and humans.

    “the α4/β2* subclass of nAChRs is necessary for the antidepressant-like effects of nicotinic antagonists as demonstrated in KO mice and using selective pharmacological agents”
3 of 3

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?

  • Long-lasting nicotine levels ensure high-affinity nAChRs repeatedly bind and unbind nicotine throughout the day.

    “This long-lasting level of nicotine ensures that high-affinity nAChRs recurrently bind and unbind nicotine throughout the day (Picciotto et al. 2008).”

    From Nicotine Withdrawal (2015) · cites this paper as Picciotto et al. 2008

    Section 1.3 reports sustained nicotine levels in chronic smokers throughout the day and says these could produce cycles of nAChR activation and desensitization. It does not establish that elevated levels ensure repeated nicotine binding and unbinding by high-affinity receptors; the same section describes potentially maintained occupancy and desensitization. No page number is available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Higher β2*-nAChR availability is thought to functionally reflect higher numbers of desensitized receptors.

    “Higher β2*-nAChR availability is thought to functionally reflect higher numbers of desensitized receptors13, 14.”

    From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [14]

  • Because desensitized nAChR conformations have higher agonist affinity, chronic nicotine exposure causes nAChRs to increasingly adopt desensitized conformations.

    “Because desensitized nAChR conformations have a higher affinity for agonist, nAChRs will increasingly adopt desensitized conformations in response to chronic nicotine exposure (Quick and Lester 2002; Picciotto et al. 2008).”

    From Nicotine Withdrawal (2015) · cites this paper as Picciotto et al. 2008

  • A network level balance between activation and desensitization is important in eliciting the behavioral effects of nicotinic compounds.

    “Current studies indicate a network level balance between activation and desensitization is important in eliciting the behavioral effects of nicotinic compounds (for review, see Picciotto et al, 2008).”

    From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Picciotto et al, 2008

  • The mechanisms behind acute and chronic actions of nicotine and related drugs in anxiety and depression models remain poorly understood.

    “However, mechanisms underlying acute and chronic effects of nicotine and other nicotinic drugs in models of anxiety and depression are not well characterized (Picciotto et al., 2008).”

    From Nicotinic Partial Agonists Varenicline and Sazetidine-A Have Differential Effects on Affective Behavior (2010) · cites this paper as Picciotto et al., 2008

Cites

Flagged first, then by citations

1 of the 173 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Couturier S, Erkman L, Valera S, Rungger D, Bertrand S, Boulter J, Ballivet M, Bertrand D. Alpha5, Alpha3 and non-alpha3, three clustered avian genes encoding neuronal acetylcholine receptor related subunits. J Biol Chem. 1990b;265:17560–7. [PubMed] [Google Scholar]

Cited by

Sorted by citations

Related

Authors
PICCIOTTO, M., ADDY, N., MINEUR, Y., & BRUNZELL, D.
Affiliations
Yale University (US)
Corresponding author
PICCIOTTO, M
ORCID
Venue
Progress in Neurobiology
Publisher
Elsevier BV
Published
2008-04
Volume
84
Issue
4
Pages
329-342
ISSN
0301-0082 (ISSN-L)
DOI
10.1016/j.pneurobio.2007.12.005
PMC
PMC2390914
OpenAlex
W2006670955
Cited by
451
References
173
Citations by year
2026: 12 · 2025: 12 · 2024: 9 · 2023: 19 · 2022: 18 · 2021: 15 · 2020: 21 · 2019: 15 · 2018: 24 · 2017: 23 · 2016: 35 · 2015: 32 · 2014: 33 · 2013: 29 · 2012: 34
FWCI
8.77
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Progress in Neurobiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
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, receptor desensitization, nicotine dependence, drug reinforcement, antidepressant-like effects, mood, smoking, emotional behavior
MeSH terms
Affect, Animals, Humans, Nicotine, Receptors, Nicotinic, Reward

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.

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