Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

May combine two claims.

At 21 days after quitting, Vt fell significantly from the 10-day value, except in thalamus, and no longer differed significantly from nonsmokers.

“Then, after 21 d of smoking cessation, the Vt values decreased significantly compared with those of the 10-d group (P , 0.01, except for thalamus), returning to the level in nonsmokers (Vt values did not show any significant difference compared with those in the nonsmokers).”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

May combine two claims.

The increase in nAChRs was similar across nearly all brain regions, but thalamus and basal ganglia followed a somewhat different pattern.

“The upregulation of the nAChRs was similar in almost all brain regions, except the thalamus and basal ganglia, which showed a slightly different pattern.”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

May combine two claims.

The average Vt at 4 h after quitting was 33.5% ± 10.5% below the nonsmoker value, and the fall was larger in thalamus (51%) and brain stem (45%).

“The mean value of the calculated Vt of the smokers was ;33.5% 6 10.5% lower than that of nonsmokers and was more pronounced in the thalamus (51%) and brain stem (45%).”

• Also stated in: § Abstract · plain

  “The binding potential of nAChRs (Vt of 123 I-5IA) in the brains of smokers decreased by 33.5% 6 10.5% after 4 h of smoking cessation”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

May combine two claims.

K1 varied somewhat across groups, but the differences were not statistically significant.

“The rate constant K 1 had some fluctuations among the different groups of volunteers (nonsmokers and smokers); however, these differences were not statistically significant (ANOVA; not significant) (Fig. 3A).”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

May combine two claims.

k2 differed significantly across groups (ANOVA P < 0.01), mainly because it was elevated in the 4-hour cessation group.

“On the other hand, the values of the rate constant k 2 were significantly different among the groups of volunteers (ANOVA; P , 0.01) (Fig. 3B).This difference was due basically to the increase of k 2 in the group with 4 h of smoking cessation.”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

May combine two claims.

In thalamus and basal ganglia at 10 days after quitting, Vt was above nonsmoker values but the difference was not significant.

“In thalamus and basal ganglia, after 10 d of smoking cessation the Vt was higher than that of the nonsmokers, as in the other regions, but was not significantly different.”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

May combine two claims.

The tracer dissociated from binding sites at different rates: the 4-hour group dissociated faster than nonsmokers, while the 10-day and 21-day groups dissociated more slowly, especially at 21 days.

“A differential dissociation of 123 I-5IA from the binding sites was noted in the brain.The 4-h smoking-cessation group showed a faster dissociation compared with that of the nonsmokers.However, the 10-d and 21-d smoking-cessation groups showed a slower dissociation than that of the nonsmokers (more pronounced in the 21-d group).”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

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

The arterial input functions were similar across all participants; plasma activity peaked 70-80 seconds after injection and fell quickly to 6.5%-29.0% of peak within 10 minutes.

“As in our previous study (19), the characteristics of the arterial input functions for all volunteers (nonsmokers and smokers) were similar.The peak plasma activity occurred between 70 and 80 s after injection in all subjects and decreased rapidly to 6.5%29.0% of the peak level in 10 min.”

• cites [19]Not matched

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

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.

May combine two claims.

The unmetabolized fraction of 123I-5IA in plasma was 87.7% ± 6.3% at 1 minute, 50.9% ± 8.8% at 20 minutes, and 32.4% ± 12.6% at 60 minutes.

“Analysis of the unmetabolized compound by TLC demonstrated a high parent fraction of 123 I-5IA in the plasma (87.7% 6 6.3%) in the first minute.123 I-5IA was rapidly metabolized, and the unchanged fraction represented 50.9% 6 8.8% and 32.4% 6 12.6% of total plasma activity at 20 and 60 min, respectively.”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.

May combine two claims.

Radioactivity peaked about 50 minutes after injection in nonsmokers and the 4-hour and 21-day groups, but about 70 minutes in the 10-day group.

“The peaks of radioactivity occurred ;50 min after injection of 123 I-5IA for nonsmokers and for the 4-h and 21-d smoking-cessation groups, whereas it was at ;70 min for the 10-d smoking-cessation group.”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

May combine two claims.

nAChR upregulation after chronic nicotine is not permanent; it returns to control levels within 7-10 days in mice and 15-20 days in rats after cessation.

“This upregulation is not permanent, returning to control levels within 7-10 d in mice (6) and 15-20 d in rats (8,9) after cessation of (2)-nicotine treatment.”

• cites [6]Not matched

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

• cites [8]Not matched

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

• cites [9]Not matched

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

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

The four groups were age-matched.

“The 4 groups were age-matched.”

Classified as probably not a substantial claim.

Chronic treatment with nicotine agonists in mice and rats causes a dose-dependent increase in nAChRs.

“Chronic treatment with agonists for most neurotransmitter receptor systems results in a decrease in receptor number.However, it has been demonstrated that chronic treatment of mice (6) and rats (7) with (2)-nicotine, an nAChR agonist, elicits a dose-dependent increase in nAChRs.”

• cites [6]Not matched

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

• cites [7]Not matched

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

Classified as probably not a substantial claim.

Staley and colleagues reported increased nAChRs in living human brain during early tobacco abstinence, measured with 123I-5IA SPECT.

“More recently, Staley et al. described the upregulation of nAChRs in human brains after early abstinence of tobacco smoking using 5-123 I-iodo-A-85380 ( 123 I-5IA) and SPECT images (13).”

• cites [13]Not matched

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

Classified as probably not a substantial claim.

Breese and colleagues found that former smokers who had quit at least two months before death had nicotinic receptor binding comparable to nonsmokers.

“Breese et al. studied the levels of 3 H-nicotine binding in humans postmortem for changes in nicotinic receptor levels and reported that the nAChR levels in smokers who had stopped smoking at least 2 mo before their death were similar to those in nonsmokers (14); the effects of shorter-term smoking cessation are unknown.”

• cites [14]Not matched

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

May combine two claims.

The tracer 123I-5IA binds with high selectivity and specificity to the α4β2 nAChR subtype in rodent and primate brain in vivo and has low acute toxicity.

“123 I-5IA is a nAChR imaging probe that has extremely high selectivity and specificity for the a4b2 subunit of nAChRs in rodent (inhibition constant 5 0.37 nM) (15) and primate brain in vivo (16), with relatively low acute toxicity (effective dose equivalent 5 30 mSv/MBq) (17,18).”

• cites [15]Not matched

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

• cites [16]Not matched

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

• cites [17]Not matched

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

• cites [18]Not matched

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

May combine two claims.

The upregulation of receptor number caused by nicotine is temporary, as also seen in rodents.

“This suggests that nicotineinduced upregulation of receptor number is a temporary effect, similar to that found in rodents (28,29).”

• Also stated in: § Abstract · plain

  “Because the upregulation of the nAChRs of the smokers after chronic exposure of the nicotine was downregulated to the nonsmokers' level by around 21 d after smoking cessation, the upregulation is a temporary effect.”

• cites [28]Not matched

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

• cites [29]Not matched

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

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

May combine two claims.

The present nonsmoker Vt values did not differ significantly from the authors' earlier published values, and K1 and k2 were likewise similar, so nonsmoker Vt was used as the reference baseline.

“To validate the Vt values of the nonsmokers as a baseline group, we compared (t test) our current data (nonsmokers) with our published data (19).No significant difference was observed between these groups.Similar findings were also seen for K 1 and k 2 .Therefore, we used the Vt values from nonsmokers as a reference for further comparisons with groups of smokers at several smoking-cessation interv”

• cites [19]Not matched

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

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.

The quote only partly states this claim.

The higher Vt at 10 days after quitting matches the nAChR upregulation reported in human postmortem and animal work.

“The result of the increased Vt of the 123 I-5IA was in agreement with the upregulation of the nAChRs in the brains of smokers reported in postmortem human studies (10)(11)(12) and in animal studies (6-9).”

• cites (10)(11)(12)Not matched

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

• cites [6]Not matched

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

• cites [7]Not matched

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

• cites [8]Not matched

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

• cites [9]Not matched

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

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

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

Individual smokers differed in how deeply and rapidly they inhaled, and this variation might have influenced the measurements.

“The smokers varied in their rate and depth of inhalation of smoke, and these interindividual differences could have affected our measurements.”

The quote only partly states this claim.

Competitive binding between radioligand and nicotine means that in vivo imaging of nAChR upregulation needs enough time for nicotine to clear, more than 4 hours after quitting.

“Because of competitive binding between the radioligand and nicotine in the brain, imaging of upregulation of nAChRs in vivo requires sufficient time for nicotine clearance (.4-h smoking cessation).”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.

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

The smokers' behavior during the cessation period was not assessed.

“We have not evaluated the smoker's behavior during the smoking-cessation period.”

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

The assay's detection limit was too high to measure all blood samples, so plasma nicotine and cotinine could not be correlated with Vt.

“The detection limit of the plasma nicotine measurements was not enough to evaluate all blood samples.Thus, we were not able to correlate the plasma nicotine/cotinine levels with Vt.”

May combine two claims.

Nicotine is very lipophilic and has substantial nonspecific uptake in the brain.

“Nicotine is highly lipophilic and demonstrated high levels of nonspecific uptake in brain (24,25).”

• cites [24]Not matched

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

• cites [25]Not matched

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

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

The design prevented a within-subject analysis of the entire group because variables were analyzed separately.

“The study design used did not allow us to deal with a within-subject analysis of the whole group, as the variables were analyzed independently.”

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

Marks and colleagues reported that the rise in rodent nicotinic receptor numbers is not due to increased mRNA levels.

“Marks et al. reported that the increase in nicotinic receptor numbers in rodents is not caused by an increase in messenger RNA levels (20).”

• cites [20]Not matched

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

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

The acute response of neuronal nAChRs to nicotine varies with their subunit composition.

“However, the characteristics of the acute response of neuronal nAChRs to nicotine depend on their subunit composition (31,32).”

• cites [31]Not matched

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

• cites [32]Not matched

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

May combine two claims.

Because nicotine did not affect receptor transcription in mice, the increase in receptor levels is probably caused by slower receptor turnover.

“The lack of an effect on nicotinic receptor transcription in mice suggests that nicotine-induced increases in nicotinic receptor levels are most likely related to a decrease in receptor turnover (21).”

• cites [21]Not matched

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

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

The thalamus has a higher density and greater heterogeneity of nicotinic receptors than other brain regions.

“Moreover, the nicotinic receptor is more abundant in the thalamus, with greater receptor heterogeneity, than in other brain regions (19).”

• cites [19]Not matched

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

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

The SPECT images were not aligned with MRI, although MRI would have been the best way to place ROIs.

“We have not coregistered SPECT images with MRI, which would have been the most appropriate method for placement of ROIs.”

May combine two claims.

The authors propose that nicotine binding and nAChR desensitization reduce cigarette craving, that craving peaks in the first 10 days because of receptor upregulation, and that it should lessen after 21 days when occupancy resembles nonsmokers.

“We believe that the nicotine binding and desensitization of the nAChRs in the brain alleviate the cigarette craving and that craving will be the worst during the first 10 d of cessation due to the upregulation of nAChRs.The craving process should minimize after 21 d, as we observe similar levels of occupancy as nonsmokers at that time.”

• AssumptionThe authors state this as an assumption: The attenuation process is homogeneous throughout the brain and can be described by an exponential function.
• AssumptionRests on an assumption: Smokers complied with the required smoking cessation periods.