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Cited by 34Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationNeuroscience and Neuropharmacology Research

Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain

Open access
Hussmann, G. Patrick, Turner, Jill R., Lomazzo, Ermelinda, Venkatesh, Rashmi, Cousins, Vanessa, Xiao, Yingxian, Yasuda, Robert P., Wolfe, Barry B. +5 more·2012·The Journal of Pharmacology and Experimental Therapeutics
DOI 10.1124/jpet.112.198085PMC PMC3477215
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Abstract

Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This up-regulation probably contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at α4β2* nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine, and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were ∼150 times its affinity for α4β2* nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not up-regulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all α4β2* nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.

AI snapshot

Written from the paper’s full text.

TL;DR

Chronic sazetidine-A (saz-A) did not up-regulate brain nicotinic acetylcholine receptors (nAChRs) in rats or mice despite reaching behaviorally active and higher doses, unlike nicotine and varenicline. Saz-A entered brain, occupied at least 75% of nAChRs, and up-regulated nAChRs in primary cortical neurons, suggesting a possible smoking-cessation strategy that desensitizes nAChRs without maintaining up-regulation.

Key findings

  • Chronic nicotine and varenicline increased nAChR density in rodent cortex/striatum, but saz-A did not: saz-A was tested at 1.6 and 4.7 mg/kg/day via osmotic minipumps and at 2.3 and 9.4 mg/kg twice daily, while nicotine (6.0 mg/kg/day or 0.7 mg/kg twice daily) and varenicline (1.2 mg/kg/day or 1.2 mg/kg twice daily) significantly up-regulated receptors.
  • Saz-A reached brain concentrations of ~30 nM during chronic infusion and 190 to 400 nM after bolus injections; its affinity for α4β2 nAChRs is ~200 pM, and receptor-occupancy estimates were approximately 75% for saz-A, 69% for varenicline, and 51% for nicotine.
  • Saz-A had low brain-to-serum ratios: after osmotic pumps, brain concentration was 0.032 µM versus serum 0.40 µM (ratio 0.08); after subcutaneous injections, brain was 0.19 or 0.42 µM versus serum 1.8 or 4.3 µM (ratios ~0.1), whereas nicotine and varenicline were concentrated in brain.
  • In rat primary cortical neurons, saz-A did up-regulate nAChRs in a concentration-dependent manner, similar to nicotine and varenicline, even at or below the ~30 nM steady-state brain concentration measured in vivo.

Methods

  • Adult male and female Sprague-Dawley rats and male 129SvJ;C57BL/6J F1 mice received chronic drug treatment for 2 weeks via osmotic minipumps or twice-daily subcutaneous injections; primary cortical neuron cultures from embryonic day 18–19 rats were treated for 10 days.
  • nAChR density was measured by radioligand binding with [3H]epibatidine or [125I]epibatidine in washed brain membranes; brain and serum drug concentrations were measured ex vivo using unwashed cortical homogenates, a modified Cheng-Prusoff equation, and competition binding assays.
  • Receptor occupancy was estimated from [3H]epibatidine association kinetics in unwashed cortical homogenates; nicotine self-administration was measured in female rats using operant licking with acute subcutaneous saz-A, and data were analyzed by ANOVA with Bonferroni or pairwise comparisons.

Limitations

  • The paper states that receptor-occupancy estimates are conservative because some drug dissociation likely occurs during the ~2.5 minutes needed to prepare tissue.
  • The paper notes that the concentration assay does not differentiate free drug from drug bound to proteins or lipids, so free saz-A may be high enough to desensitize brain nAChRs but not high enough to trigger up-regulation in the endoplasmic reticulum.
  • The paper acknowledges a potential confound if [3H]epibatidine bound up-regulated nAChRs at a different rate, but argues this is unlikely based on prior data; evident from the text, the proposed mechanism for the in vivo/in vitro dichotomy is not directly tested, and the findings are limited to rodent and cultured-neuron models.

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

Integrity signals

Registry

Crossref · 10.1124/jpet.112.198085

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 47 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In rat primary cortical cultures, pharmacologically relevant concentrations of nicotine and varenicline up-regulated nAChRs by 2.5- to 3-fold.

    “pharmacologically relevant concentrations of nicotine and varenicline up-regulated nAChRs by 2.5-to 3-fold, similar to the up-regulation observed in brain after chronic administration of these drugs.”
    Quote in the paperSubstantial claim
  • Findingown data

    Chronic administration of saz-A at behaviorally active and higher doses does not up-regulate nAChRs in rodent brain.

    “We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains.”
    • Also stated in: § Up-Regulation of nAChRs in Rodent Brain. · plain
      “neither a low dose (1.6 mg/kg/day) nor a high dose (4.7 mg/kg/day) of saz-A, both of which are behaviorally active (Johnson et al., 2012), increased these receptors.”
    • Also stated in: § Discussion · plain
      “neither continuous infusion of saz-A nor bolus injections twice daily for 2 weeks increased the density of nAChRs in rat or mouse brain.”
    Quote in the paperSubstantial claim
  • Findingown data

    During two weeks of continuous saz-A infusion, the drug's steady-state level in brain was under one-tenth of its level in blood.

    “These studies indicated that during chronic infusion of saz-A for 2 weeks its steady-state concentration in brain was less than 10% of that in blood.”
    Quote in the paperSubstantial claim
  • Findingown data

    After two weeks of twice-daily saz-A injections, the brain level measured ten minutes after the final dose was also roughly one-tenth of the blood level.

    “Likewise, after 2 weeks of twice-daily injections of saz-A, its brain concentration 10 min after the last injection was also approximately only 10% that of blood”
    Quote in the paperSubstantial claim
  • Findingown data

    Saz-A reached brain concentrations that were approximately 150 times its affinity for α4β2* nAChRs.

    “Our results indicate that saz-A reached concentrations in the brain that were ϳ150 times its affinity for ␣4␤2* nAChRs”
    Quote in the paperSubstantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingown data

    Full saturation curves with [3H]EB in rat cortex confirmed that saz-A treatment did not increase nAChR density and did not alter [3H]EB affinity.

    “Full saturation curves with [ 3 H]EB in rat cortex (Fig. 1D) confirmed that treatment with saz-A did not increase the density of the receptors and also demonstrated that the affinity of [ 3 H]EB was not altered”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Saz-A also up-regulated nAChRs in primary cortical neurons in a concentration-dependent manner, similar to nicotine and varenicline, even at or below steady-state brain concentrations (30 nM).

    “saz-A also up-regulated nAChRs in primary cortical neurons.The up-regulation by saz-A was concentration-dependent and resulted in an in-crease in nAChRs that was similar to the increases produced by nicotine and varenicline.Moreover, saz-A up-regulated receptors even at or below the steady-state concentrations measured in the rat brain (30 nM).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After twice-daily subcutaneous injections, 10 min after the last injection, brain concentrations of nicotine and varenicline were 8.9 and 4.2 M, whereas saz-A brain concentrations were 0.19 and 0.42 M after 2.3 and 9.4 mg/kg.

    “The brain concentrations of nicotine and varenicline were 8.9 and 4.2 M, whereas the brain concentrations of saz-A after the two doses were 0.19 and 0.42 M, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In female rat cortex, chronic nicotine (6.0 mg/kg/day) and varenicline (1.2 mg/kg/day) increased nAChRs, but saz-A (4.7 mg/kg/day) did not.

    “In female rat cortex (Fig. 1C), chronic administration of both nicotine (6.0 mg/kg/day) and varenicline (1.2 mg/kg/ day) increased nAChRs, but saz-A at a dose of 4.7 mg/kg/day did not.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nicotine and varenicline were concentrated in brain over serum by approximately 2.5- and 1.5-fold, respectively, whereas saz-A reached a brain concentration only 8% of its serum concentration.

    “Thus, nicotine and varenicline were concentrated in brain over serum by approximately 2.5-and 1.5-fold, respectively.In contrast, saz-A reached a concentration in brain that was only 8% its concentration in serum (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mice, chronic nicotine (18 mg/kg/day) and varenicline (1.8 mg/kg/day) significantly increased nAChRs in cerebral cortex, but saz-A at 1.8 and 3.6 mg/kg/day did not.

    “In mice chronic administration of both nicotine (18 mg/kg/ day) and varenicline (1.8 mg/kg/day) via osmotic minipumps significantly increased nAChRs in the cerebral cortex (the higher dose of nicotine was used to account for the very rapid metabolism of nicotine in the mouse; Marks et al., 1983); but again, saz-A at doses of 1.8 and 3.6 mg/kg/day did not increase the receptors (Fig. 1E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After twice-daily injections, nicotine and varenicline were concentrated in brain over serum by 9.5- and 2.8-fold, whereas saz-A only reached a brain concentration approximately 10% of serum.

    “Thus, 10 min after injection nicotine and varenicline were concentrated in brain over serum by 9.5-and 2.8-fold, respectively, whereas, again, saz-A only reached a concentration in brain approximately 10% its concentration in serum (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The binding maxima in tissues from rats treated with nicotine or varenicline were approximately 2-fold higher than saline, whereas saz-A values were nearly the same as saline.

    “Thus, the binding maxima in tissues from rats treated with nicotine or varenicline were ϳ2-fold higher than those from rats treated with saline, whereas the values from rats treated with saz-A were nearly the same as those from the rats treated with saline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The key finding was that nAChRs from saz-A-treated rats, which were not upregulated, were indeed occupied by the drug.

    “Moreover, the key finding in this experiment was that nAChRs from saz-A-treated rats, which were not upregulated, were indeed occupied by the drug.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Twice-daily subcutaneous nicotine (0.7 mg/kg) and varenicline (1.2 mg/kg) significantly increased cerebral cortical nAChRs, whereas saz-A at 2.3 or 9.4 mg/kg did not.

    “Both nicotine and varenicline administered twice daily significantly increased cerebral cortical nAChRs; whereas, again in contrast, saz-A even at doses four to six times behaviorally active doses did not up-regulate these receptors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After 14 days of chronic administration via osmotic pumps, steady-state brain concentrations were nicotine 2.2 M, varenicline 0.66 M, and saz-A 0.032 M.

    “The steady-state concentrations of nicotine, varenicline, and saz-A in brain were calculated to be 2.2, 0.66, and 0.032 M, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although saz-A entered brain poorly, it still reached roughly 30 nM in brain with chronic infusion and 190 to 400 nM after bolus dosing.

    “Despite its relatively low penetration into brain, saz-A reached a steady-state concentration in brain of ϳ30 nM during chronic infusion and 190 to 400 nM after bolus injections.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nicotine and varenicline, by contrast, reached high brain concentrations under both chronic infusion and chronic intermittent administration.

    “This is in marked contrast to both nicotine and varenicline, which were highly concentrated in brain during both methods of chronic administration”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The [3H]EB Ki values for nicotine, varenicline, and saz-A in cortical homogenates were 15.6 nM, 1.13 nM, and 178 pM, respectively.

    “The K i values, calculated from the fitted curves, were as follows: nicotine, 15.6 Ϯ 1.0 nM; varenicline, 1.13 Ϯ 0.20 nM; and sazetidine-A, 178 Ϯ 10 pM.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nicotine, varenicline, and saz-A each increased nicotinic receptor levels in cultured primary cortical neurons.

    “Nicotine-, varenicline-, and sazetidine-A-induced nAChR up-regulation in primary neurons in culture.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    Nicotine and varenicline maintain elevated nicotinic receptor levels in rat and mouse brain during chronic treatment.

    “if nicotine and varenicline replacement therapies sustain the increased nAChRs in human brain during smoking cessation treatment, as they do in rat and mouse brain”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Increased nAChRs are seen with in vivo imaging in baboon brain after chronic nicotine and in the brains of current smokers.

    “Increased nAChRs are also seen with in vivo imaging techniques in baboon brain after chronic administration of nicotine (Kassiou et al., 2001) and the brains of current smokers (Staley et al., 2006;Wu ¨llner et al., 2008).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kassiou et al., 2001 source

      Not checked in the free run.

    • cites Staley et al., 2006 source

      Not checked in the free run.

    • cites Wu ¨llner et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These findings introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing long-term abstinence.

    “and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The rodent brain up-regulation model is predictive of human smoking cessation outcomes.

  • May combine two claims.

    Interpretationown data

    Chronic saz-A did not upregulate nAChRs despite reaching brain concentrations known to bind and desensitize virtually all α4β2* nAChRs in brain.

    “Thus, chronic administration of saz-A did not upregulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all ␣4␤2* nAChRs in brain.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    The present saz-A brain-to-blood concentration finding matches an earlier mouse study that measured these concentrations after one intraperitoneal dose.

    “which agrees with a recent study that measured brain and blood concentrations of saz-A in mice after a single intraperitoneal injection (Caldarone et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Caldarone et al., 2011 source

      Not checked in the free run.

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

    Premisecitation

    Saz-A reduces alcohol consumption.

    “reduces alcohol consumption (Rezvani et al., 2010)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rezvani et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Saz-A potently and selectively desensitizes α4β2 nAChRs.

    “Saz-A also potently and selectively desensitizes these receptors (Xiao et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xiao et al., 2006 source

      Not checked in the free run.

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

    Premisecitation

    Saz-A is a partial agonist at α4β2 nAChRs that may show differential efficacy depending on receptor stoichiometry.

    “Sazetidine-A [saz-A; 6-(5-(((S)-azetidin-2-yl)methoxy)pyridin-3-yl)hex-5-yn-l-ol] is a partial agonist at ␣4␤2 nAChRs that may show differential efficacy at this receptor subtype depending on the stoichiometry (Zwart et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zwart et al., 2008 source

      Not checked in the free run.

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

    Premisecitation

    Saz-A increases performance on tasks of attention, even after attention is disrupted by scopolamine or MK801.

    “increases performance on tasks of attention, even after attention is disrupted by pretreatment with scopolamine or dizocilpine [(5S,10R)-(ϩ)-5methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10imine] (MK801) (Rezvani et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rezvani et al., 2011 source

      Not checked in the free run.

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

    Premisecitation

    In preclinical tests, saz-A produces behavior indicative of potential antidepressant and/or antianxiety effects.

    “in preclinical tests saz-A produces behavior indicative of potential antidepressant and/or antianxiety effects (Kozikowski et al., 2009;Turner et al., 2010Turner et al., , 2011;;Caldarone et al., 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kozikowski et al., 2009 source

      Not checked in the free run.

    • cites Turner et al., 2010 source

      Not checked in the free run.

    • cites Caldarone et al., 2011 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The assay cannot separate unbound drug from drug associated with proteins or lipids.

    “because our assay does not differentiate between free drug and that bound to proteins or lipids”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Drugs like saz-A, which desensitize nicotinic receptors without raising their density, might help increase smoking cessation rates in both the short and long term.

    “The studies here indicate that drugs such as saz-A that can desensitize nAChRs without increasing their density might provide a means to increase smoking cessation rates during both the short term and, more importantly, over the long term.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The interplay between up-regulation and desensitization may be important in, or even underlie, nicotine addiction and withdrawal responses during abstinence.

    “Thus, the dynamics between these two effects of nicotine may play a crucial role in or even underlie nicotine addiction and/or the withdrawal responses that occur during abstinence.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    The brain levels and brain-to-blood ratios for nicotine and varenicline matched values reported in earlier work.

    “moreover, both the concentrations and the brain-to-blood ratios of nicotine and varenicline were similar to previously reported values (Ghosheh et al., 1999;Doura et al., 2008;Rollema et al., 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ghosheh et al., 1999 source

      Not checked in the free run.

    • cites Doura et al., 2008 source

      Not checked in the free run.

    • cites Rollema et al., 2010 source

      Not checked in the free run.

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

    Interpretationreasoning

    Those later increased responses probably result from receptor resensitization after nicotine levels fall sufficiently.

    “which probably reflects the resensitization of the receptors once the nicotine concentrations decrease sufficiently.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Saz-A can enter brain well enough to act on and desensitize surface nicotinic receptors and thereby influence behavior, but it cannot cross membranes well enough to enter neurons and reach the endoplasmic reticulum.

    “we propose that saz-A can enter the brain well enough to act at and desensitize cell surface nAChRs and thus affect behaviors, but it does not cross membranes well enough to traverse the plasma membrane to enter neurons and then negotiate the additional membranes to enter sites within the endoplasmic reticulum”
    Quote in the paperSubstantial claim

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

    Premisecitation

    After chronic nicotine treatment, increased responses that reflect the higher receptor numbers are usually observed later.

    “Subsequently, however, increased responses reflecting the increased receptors are usually found (Rowell and Wonnacott, 1990;Benwell et al., 1995;Gopalakrishnan et al., 1996Gopalakrishnan et al., , 1997;;Buisson and Bertrand, 2001;Avila et al., 2003)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Rowell and Wonnacott, 1990

      Not checked in the free run.

    • cites Benwell et al., 1995 source

      Not checked in the free run.

    • cites Gopalakrishnan et al., 1996 source

      Not checked in the free run.

32 of 32

  • The paper relies on this without support.

    nAChR up-regulation is triggered at the ligand binding site.

    “nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain.”

  • The paper relies on this without support.

    The rodent brain up-regulation model is predictive of human smoking cessation outcomes.

    “introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.”

  • The paper relies on this without support.

    Saz-A has an affinity of about 200 pM for α4β2 nicotinic receptors.

    “The affinity of saz-A for ␣4␤2 nAChRs is ϳ200 pM”

  • The authors state this as an assumption.

    In the proposed model, the increased nicotinic receptors in a smoker's brain are relatively inactive during low neural activity.

    “In this model, the increased nAChRs in a smoker's brain are relatively silent during periods of low neural activity (e.g., sleep)”

  • The authors state this as an assumption.

    In the proposed model, upon waking, acetylcholine activation of the increased receptors triggers arousal and anxiety.

    “when the relevant brain pathways are stimulated by acetylcholine signaling (e.g., in the reticular activating system upon waking), the increased receptors convey excess levels of neural activity, which triggers anxiety pathways that lead to craving.”

  • The authors state this as an assumption.

    In the proposed model, smoking a cigarette desensitizes nicotinic receptors, lowering cholinergic signaling and anxiety.

    “The rapid bolus of nicotine desensitizes the nAChRs, resulting in decreased levels of cholinergic signaling and decreased anxiety, i.e., the craving is satisfied.”

  • The authors state this as an assumption.

    In the proposed model, as nicotine levels fall, the receptors resensitize, and excess signaling from the increased receptors cues the next cigarette.

    “However, as the nicotine concentration in the brain falls, the nAChRs become resensitized, and again the excess level of activities mediated by the increased number of nAChRs provides the signal for the next cigarette.”

  • The authors state this as an assumption.

    In the proposed model, this cycle is a manifestation of nicotine addiction.

    “This establishes a continuous cycle at the cellular level that is reflected in the behavior we call addiction.”
8 of 8

Claims other papers make about this one

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting radioligand concentration ranges for saturation assays

    Minor

    The methods give a range of 5 to 3500 pM for saturation binding assays, but the caption for the unwashed-homogenate saturation assay in Fig. 4A gives 2 to 4000 pM.

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Authors
Hussmann, G. P., Turner, J. R., Lomazzo, E., Venkatesh, R., Cousins, V., Xiao, Y., Yasuda, R. P., Wolfe, B. B., Perry, D. C., Rezvani, A. H., Levin, E. D., Blendy, J. A., & Kellar, K. J.
Affiliations
Duke University (US)
ORCID
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2012-11
Volume
343
Issue
2
Pages
441-450
ISSN
0022-3565 (ISSN-L)
DOI
10.1124/jpet.112.198085
PMC
PMC3477215
OpenAlex
W2106076742
Semantic Scholar
95f9dea5de7ec2673ea0867070b3fc4327225cad
Cited by
34
References
67
Citations by year
2021: 1 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 9 · 2013: 9 · 2012: 1
FWCI
3.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (DA027990)
  • National Institute on Drug Abuse (F32DA026236, DA012976, R00DA032681, U19DA027990, K99DA032681, DA027990, R01DA012976, R56DA012976, R01DA015767, DA015767)
  • National Cancer Institute (CA-143187, P50CA143187)
  • National Institute on Minority Health and Health Disparities (L60 MD006479)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
nicotinic acetylcholine receptors, alpha4beta2 nAChR, receptor up-regulation, chronic drug administration, nicotine dependence, nicotine self-administration, varenicline, smoking cessation, receptor occupancy, receptor desensitization
MeSH terms
Varenicline, Animals, Azetidines, Behavior, Animal, Benzazepines, Binding Sites, Brain Chemistry, Cerebral Cortex, Dose-Response Relationship, Drug, Female, Male, Membranes, Neurons, Nicotine, Pregnancy, Pyridines, Quinoxalines, Receptors, Nicotinic, Self Administration, Up-Regulation, Rats, Sprague-Dawley, Nicotinic Agonists, Rats

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

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

Statistics and arithmetic are recomputed, not judged.

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

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

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