CoChat
Sign Up
Cited by 135Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationRadiopharmaceutical Chemistry and Applications

Greater Nicotinic Acetylcholine Receptor Density in Smokers Than in Nonsmokers: A PET Study with 2-18F-FA-85380

Open access
Mukhin, Alexey G., Kimes, Alane S., Chefer, Svetlana I., Matochik, John A., Contoreggi, Carlo S., Horti, Andrew G., Vaupel, D. Bruce, Pavlova, Olga +1 more·2008·Journal of Nuclear Medicine
DOI 10.2967/jnumed.108.050716PMC PMC2766917
Open this paper in CoChat — free accountOpen PDF

Abstract

UNLABELLED: Assays of human postmortem brain tissue have revealed that smokers have greater densities of high-affinity nicotinic acetylcholine receptors (nAChRs) in several brain regions than do nonsmokers or exsmokers. Quantitative PET imaging of nAChRs in humans has recently been reported using the alpha4beta2* subtype-specific radioligand 2-(18)F-FA-85380 (2FA). METHODS: We used PET and 2FA to measure total volumes of distribution corrected for the free fraction of 2FA in plasma (V(T)/f(P)) in 10 nonsmokers and 6 heavy smokers (>14 cigarettes/d; abstinent for >36 h). Dynamic PET scans were performed over 8 h, commencing immediately after a bolus injection of 2FA. Anatomic sampling was performed on PET images that were coregistered to MR images acquired from each volunteer. Data were analyzed by Logan plots and by 1- and 2-tissue-compartment models using unbound, unmetabolized arterial 2FA concentration as the input function. RESULTS: All modeling methods yielded similar results. V(T)/f(P) was significantly higher in smokers than in nonsmokers in all brain regions tested, except the thalamus. We used measures of V(T)/f(P) and estimates of nondisplaceable volume of distribution and found 25%-200% higher values in smokers than in nonsmokers for the volume of distribution for the specific binding compartment in the frontal cortex, midbrain, putamen, pons, cerebellum, and corpus callosum. These findings were consistent with voxel-based analysis using statistical parametric mapping. CONCLUSION: Our findings suggest that PET with 2FA can be used to study the role of nicotine-induced upregulation of nAChRs in active smokers and during smoking cessation.

AI snapshot

Written from the paper’s full text.

TL;DR

PET with 2-18F-FA-85380 found greater α4β2* nicotinic acetylcholine receptor distribution volumes in heavy smokers than in nonsmokers across most brain regions, except the thalamus. The authors conclude this method can quantify smoking-related nAChR upregulation in vivo.

Key findings

  • In 6 heavy smokers versus 10 nonsmokers, total volume of distribution corrected for free plasma fraction (VT/fP) was significantly higher in smokers in all tested brain regions except the thalamus (P < 0.01, 1-tailed t test with Bonferroni correction).
  • Estimated specific binding compartment values (VS/fP) were 25%–200% higher in smokers than nonsmokers for frontal cortex, midbrain, putamen, pons, cerebellum, and corpus callosum, assuming equal nondisplaceable volume of distribution (VND/fP) and using VND/fP values from 3.5 to 5.
  • Statistical parametric mapping confirmed greater VT/fP in smokers across almost the entire brain except the thalamus; no brain region showed the reverse pattern.
  • The greatest absolute differences were in cerebellum, midbrain, and pons; the greatest percentage differences were in corpus callosum, cerebellum, and frontal cortex, with the smallest difference in thalamus.

Methods

  • Participants were healthy smokers (n = 6; 1 woman; age 33 ± 8 y; smoking 15–30 cigarettes/d, 19 ± 2.9; abstinent 36–48 h) and healthy nonsmokers (n = 10; 4 women, 1 exsmoker; age 28 ± 8 y).
  • Dynamic PET scans lasted 8 h after bolus injection of 2-18F-FA-85380, with arterial blood sampling; PET images were coregistered to each volunteer’s MRI for anatomic sampling.
  • VT/fP was calculated for 7 brain regions using Logan plots and 1- and 2-tissue-compartment models with unbound, unmetabolized arterial 2FA as input; voxel-based SPM used a 2-sample t test with voxelwise P < 0.01 and minimum cluster size of 100 contiguous voxels.

Limitations

  • The paper states that VT/fP is not a direct measure of receptor density and includes both specific and nonspecific radioligand accumulation; k3 and k4 from the 2-tissue-compartment model were poorly identified, and VND/fP was not determined by receptor blocking but assumed equal in smokers and nonsmokers.
  • The paper also notes possible residual nicotine or a longer-lived nicotine metabolite competing for binding, and that its smokers smoked fewer cigarettes/day than those in Breese et al.
  • Evident from the text: the sample was small (6 smokers, 10 nonsmokers), the design was cross-sectional, and the 36–48 h abstinence period may not capture initial receptor density differences.

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

Integrity signals

Registry

Crossref · 10.2967/jnumed.108.050716

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The rate constants k3 and k4 for 2FA from the two-tissue-compartment model were poorly identified.

    “As reported previously (26), we also found that k3 and k4 for 2FA obtained using the 2-tissue-compartment model were poorly identified (data not shown).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] 2005, J Nucl Med.

      Not checked in the free run.

  • Findingown data

    None of the differences in the three pairs of plasma curves between smokers and nonsmokers was statistically significant.

    “None of the differences in the 3 pairs of plasma curves between smokers and nonsmokers was significant.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    The magnitude of VT/fP differences between smokers and nonsmokers in this PET study was similar to that found in a recent SPECT study.

    “The magnitude of the differences in VT/fP between smokers and nonsmokers was similar to that found in a recent SPECT study (28).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] source

      Not checked in the free run.

  • Findingcitation

    The lack of thalamic increase in this study disagrees with a postmortem study that found Bmax in smokers almost twice that in nonsmokers.

    “This lack of increase in the thalamus is not in agreement with the observations in a study of postmortem tissue showing values for the Bmax in smokers that were almost 2-fold those in nonsmokers (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] 1997, J Pharmacol Exp Ther. source

      Not checked in the free run.

  • Findingcitation

    Almost no difference in thalamic VT/fP was found in both the present PET study and the recent SPECT study.

    “In that study and in the present PET study, almost no difference in VT/fP in the thalamus was demonstrated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] source

      Not checked in the free run.

  • May combine two claims. 11
  • Classified as probably not a substantial claim. 14
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    The largest absolute VT/fP differences between smokers and nonsmokers were in cerebellum, midbrain, and pons, followed by putamen, frontal cortex, and thalamus, with corpus callosum showing the smallest difference.

    “As shown, the greatest absolute differences between nonsmokers and smokers were in the cerebellum, midbrain, and pons, followed by the putamen, frontal cortex, and thalamus; the corpus callosum showed the smallest difference.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Total plasma radioactivity tended to be greater in smokers than in nonsmokers.

    “Comparing the standardized uptake value (SUV) in the arterial plasma of smokers with that in the arterial plasma of nonsmokers revealed that total plasma radioactivity tended to be greater in smokers than in nonsmokers (Fig. 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The fraction of unmetabolized 2FA was lower in smokers, reaching 52% ± 3% versus 56% ± 4% in nonsmokers at 8 hours after injection.

    “In contrast, the fraction of radioactivity that corresponded to unmetabolized 2FA was lower in smokers, especially at later time points, reaching 52% ± 3% of total radioactivity for smokers and 56% ± 4% for nonsmokers at 8 h after injection (Fig. 2).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In 6 heavy smokers abstinent for more than 36 hours compared with 10 nonsmokers, VT/fP was significantly higher in smokers in all tested brain regions except the thalamus.

    “VT/fP was significantly higher in smokers than in nonsmokers in all brain regions tested, except the thalamus.”
    • Also stated in: § Radioactivity in Plasma and Brain Tissue · plain
      “All these differences, except that in the thalamus, were statistically significant (P < 0.01, 1-tailed t test with Bonferroni correction for multiple comparisons).”
    • Also stated in: § Discussion · plain
      “We observed significantly greater values (P < 0.01 by a 1-tailed t test with Bonferroni correction) for VT/fP in smokers than in nonsmokers in all the specifically evaluated brain structures, except the thalamus.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The three modeling approaches used for volume-of-interest analysis produced similar total distribution volume corrected for free plasma fraction values for each examined brain region.

    “All modeling methods yielded similar results.”
    • Also stated in: § Radioactivity in Plasma and Brain Tissue · plain
      “Similar VT/fP values for each of the regions mentioned were obtained from the 3 modeling procedures used in the VOI analysis (nonsmokers, Fig. 4A; smokers, Fig. 4B); however, a tendency for values calculated with the 2-tissue-compartment model to give slightly higher values for both groups was demonstrated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When absolute differences were expressed as percentages of nonsmoker values, the largest percentage differences were in corpus callosum, followed by cerebellum and frontal cortex; midbrain and pons were moderate, and thalamus was smallest.

    “When the absolute differences were converted to percentage of values in nonsmokers, the greatest percentage differences were observed in the corpus callosum, followed by the cerebellum and frontal cortex. The percentage differences in the midbrain and pons were moderate, and those in the thalamus were smallest.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The in vivo results are consistent with in vitro data and suggest that PET with 2FA provides a reliable method for further testing the role of nAChR density in smoking behavior and smoking cessation.

    “The in vivo results of this study are consistent with in vitro data and suggest that PET studies with 2FA provide a reliable method for further testing the role of nAChR density in smoking behavior and smoking cessation.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Nicotine is unlikely to change the tissue composition responsible for nonspecific accumulation of 2FA.

    “First, nicotine is unlikely to change the tissue composition responsible for nonspecific accumulation of 2FA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Taken together, results from two published SPECT studies and this PET study suggest that greater receptor density in smokers declines over the first 3 weeks after smoking cessation and approaches nonsmoker levels.

    “Taken together, results from 2 published SPECT studies (28,30) and the current PET study suggest that the greater receptor density in smokers declines over the first 3 wk after smoking cessation and approaches the level observed in nonsmokers.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] source

      Not checked in the free run.

    • cites [30] source

      Not checked in the free run.

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

    Study design and conductown data

    Smoking abstinence duration was established by participant self-report and confirmed by carbon monoxide monitoring on arrival and again 2-3 hours before PET; carbon monoxide levels were 0-3 ppm on the morning of the scan.

    “The duration of smoking abstinence was established by participant self-report and confirmed by CO monitoring on arrival at the unit and again 2–3 h before the PET scan. CO levels ranged from 0 to 3 ppm on the morning of the scan.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Brody et al. reported that nicotine from smoking to satiety occupies 95% of nAChRs and that smoking a single cigarette reduces available receptors by 88%.

    “Brody et al. (31) reported that nicotine from smoking to satiety occupies 95% of nAChRs in a study using 2FA as the radioligand. Smoking a single cigarette reduces available receptors by 88% (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] source

      Not checked in the free run.

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

    Interpretationcitation

    The similarity in VT/fP changes between this PET study and the SPECT 5IA study was somewhat unexpected.

    “As mentioned, the observed changes in VT/fP were similar to those observed with SPECT and 5IA as the radioligand (28). This similarity was somewhat unexpected.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] source

      Not checked in the free run.

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

    Premisecitation

    Postmortem tissue studies observed receptor densities in exsmokers similar to those in nonsmokers after more than 2 months of smoking cessation.

    “Receptor densities in exsmokers that were similar to those in nonsmokers after more than 2 mo of smoking cessation were observed previously in postmortem tissue (5,6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] 1997, J Pharmacol Exp Ther. source

      Not checked in the free run.

    • cites [6] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another 5IA SPECT study showed that smoker values at 10 days after cessation were only 8%-26% above nonsmokers, and at 21 days were similar to nonsmokers.

    “Additional support for the suggestion that data acquired at 7 d after the onset of smoking cessation reflect the decline in nAChRs at that time point comes from another study using 5IA (30), which showed that values for smokers at 10 d after the onset of smoking cessations were only 8%–26% above those for nonsmokers, and at 21 d values were similar to those for nonsmokers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    This study did not determine the nondisplaceable volume of distribution corrected for free plasma fraction by blocking receptors.

    “Within the context of this study, we did not determine the VND/fP by blocking the receptors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Even if 2FA metabolism is slightly faster in smokers, additional accumulation of radiolabeled metabolites in smokers' brains is unlikely, because rodent studies showed practically no accumulation of 2FA metabolites in brain.

    “Second, even if the rate of metabolism for 2FA is slightly greater in smokers than in nonsmokers, additional accumulation of radiolabeled metabolites in the brains of smokers leading to an increase in apparent VND/fP is unlikely, as data from our studies in rodents (Alexey G. Mukhin and D. Bruce Vaupel, unpublished data, 2005) showed practically no accumulation of 2FA metabolites in brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Assuming a monoexponential decline, the half-life for the decline is between 3 and 6 days, and receptor densities measured at 2, 7, and 11 days after cessation probably underestimate initial differences by about 20%, 60%, and 75%, respectively.

    “With the assumption that this decline can be described by a monoexponential function, these results suggest that the half-life for this decline is between 3 and 6 d and that receptor densities assayed in smokers at 2, 7, and 11 d after cessation probably underestimate the initial receptor density differences between nonsmokers and smokers by approximately 20%, 60%, and 75%, respectively.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The decline in receptor density after smoking cessation can be described by a monoexponential function.

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

    Study design and conductnone given

    The radiochemical purity of 2FA was greater than 95%.

    “The radiochemical purity of 2FA was greater than 95%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    VT/fP is not a direct measure of receptor density because it includes both specific and nonspecific components of radioligand accumulation.

    “Nevertheless, VT/fP is not a direct measure of receptor density; it includes both specific and nonspecific components of radioligand accumulation.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    A possible explanation for the thalamic discrepancy is that this study's smokers smoked fewer cigarettes per day (15-30) than those in Breese et al. (10-60).

    “A possible explanation is that the smokers in our study smoked fewer cigarettes/d (i.e., 15–30) than the smokers in the study by Breese et al. (10–60 cigarettes/d) (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] 1997, J Pharmacol Exp Ther. source

      Not checked in the free run.

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

    Study design and conductnone given

    Smokers abstained from smoking for 36-48 hours before each scan, approximately 15 nicotine half-lives.

    “Smokers abstained from smoking 36–48 h before each scan (∼15 half-lives for nicotine).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In rodents, the difference in receptor density between nicotine and saline treatment is dose-dependent, and only high nicotine doses significantly increase thalamic nAChRs.

    “In rodents, the difference in receptor density between nicotine and saline treatment is related to nicotine exposure in a dose-dependent fashion, and only high doses of nicotine are associated with significant increases in nAChRs in the thalamus (32).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] 1991, J Pharmacol Exp Ther. source

      Not checked in the free run.

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

    Premisecitation

    In nicotine-treated mice, nAChR upregulation disappears 8 days after treatment termination.

    “In nicotine-treated mice, the upregulation of nAChRs disappears 8 d after treatment termination (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] 1985, J Pharmacol Exp Ther.

      Not checked in the free run.

23 of 23

  • The authors state this as an assumption.

    The average nondisplaceable volume of distribution corrected for free plasma fraction is the same in smokers and nonsmokers.

    “assuming that the average VND/fP values for smokers and nonsmokers were the same”
    “The assumption of equal VND/fP in smokers and nonsmokers is appropriate for 2 reasons.”

  • The authors state this as an assumption.

    The decline in receptor density after smoking cessation can be described by a monoexponential function.

    “With the assumption that this decline can be described by a monoexponential function”

  • The authors state this as an assumption.

    The effective concentration of nicotine to occupy 50% of the receptors labeled by 2FA in humans is 0.87 ng/mL.

    “Assuming that the effective concentration to occupy 50% of the receptors labeled by 2FA in humans is 0.87 ng/mL (31)”
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?

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.

  • Reported smoking-rate SD is incompatible with the range and sample size

    Minor

    With six smokers and a mean of 19 cigarettes/day, a smoker at the reported maximum of 30 is 11 above the mean. That single observation would require a sample SD of at least 4.9 cigarettes/day, so the reported SD of 2.9 is impossible.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. 2002, MMWR Morb Mortal Wkly Rep., 51, 300
  2. Westman EC, Rose JE. Nicotine replacement therapies and beyond. In: Piasecki M, Newhouse P, eds. Nicotine in Psychiatry. Washington, DC: American Psychiatric Press; 1999:215–233.
  3. 2003, J Nucl Med., 44, 596
  4. 1973, Psychopharmacol Bull., 9, 13
  5. 2005, J Nucl Med., 46, 240
  6. 2000, J Nucl Med., 41, 1552
  7. 1985, J Pharmacol Exp Ther., 235, 619

Cited by

Sorted by citations

Related

Authors
Mukhin, A. G., Kimes, A. S., Chefer, S. I., Matochik, J. A., Contoreggi, C. S., Horti, A. G., Vaupel, D. B., Pavlova, O., & Stein, E. A.
Affiliations
  • National Institutes of Health (US)
  • Johns Hopkins University (US)
  • United States Department of Health and Human Services (US)
ORCID
Venue
Journal of Nuclear Medicine
Publisher
Society of Nuclear Medicine
Published
2008-09-15
Volume
49
Issue
10
Pages
1628-1635
ISSN
  • 0161-5505 (ISSN-L)
  • 2159-662X
DOI
10.2967/jnumed.108.050716
PMC
PMC2766917
OpenAlex
W2131967049
Semantic Scholar
ee7e15f43f56262513957f6f6e569c102a74d4e3
Cited by
135
References
38
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 8 · 2015: 14 · 2014: 12 · 2013: 19 · 2012: 13
FWCI
3.84
Type
journal article
Language
en
Open access
Locations
  • Journal of Nuclear Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Drug Abuse (Z01DA000405)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
Keywords
nicotinic acetylcholine receptors, smoking, PET radiotracer, receptor density, smoking cessation, brain receptor binding, Logan plot
MeSH terms
Adult, Azetidines, Brain, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nicotine, Pyridines, Receptors, Nicotinic, Smoking, Time Factors, Reproducibility of Results, Radiopharmaceuticals, Positron-Emission Tomography

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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 ›

Are you an author, or do you see a problem with this page? Request a review