Parallel Anxiolytic-Like Effects and Upregulation of Neuronal Nicotinic Acetylcholine Receptors Following Chronic Nicotine and Varenicline
Open accessAbstract
INTRODUCTION: Clinical and preclinical studies suggest that regulation of nicotinic acetylcholine receptors (nAChR) maybe involved in the etiology of withdrawal symptoms. METHODS: We evaluated heteromeric nAChR regulation via [³H]epibatidine binding following cessation of chronic nicotine or varenicline treatment. Animals were concurrently tested in the marble-burying test to evaluate treatment-related effects. RESULTS: We found that both nicotine (18 mg/kg/day, free base) and varenicline (1.8 mg/kg/day) chronically administered for 14 days upregulated nAChRs significantly in the cortex, hippocampus, striatum, and thalamus. The duration of upregulation (up to 72 hr) was both drug and region specific. In addition to nAChR upregulation, chronic administration of both nicotine and varenicline had anxiolytic-like effects in the marble-burying test. This effect was maintained for 48 hr following cessation of varenicline but was absent 24 hr following cessation from nicotine. Additionally, marble-burying behavior positively correlated to the regulation of cortical nAChRs following cessation of either treatment. CONCLUSIONS: Varenicline has been shown to be an efficacious smoking cessation aid, with a proposed mechanism of action that includes modulation of dopamine release in reward areas of the brain. Our studies show that varenicline elicits both anxiolytic effects in the marble-burying test as well as region- and time-specific receptor upregulation. These findings suggest receptor upregulation as a mechanism for its efficacy as a smoking cessation therapy.
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TL;DR
Chronic nicotine and varenicline both upregulate heteromeric nicotinic acetylcholine receptors and produce anxiolytic-like effects in the mouse marble-burying test, with varenicline’s effects lasting longer after cessation. Cortical nAChR upregulation correlates with marble-burying behavior, suggesting receptor regulation may contribute to varenicline’s smoking-cessation efficacy.
Key findings
- Chronic nicotine (18 mg/kg/day, free base) and varenicline (1.8 mg/kg/day) administered for 14 days significantly upregulated nAChRs in cortex, hippocampus, striatum, and thalamus, measured by [3H]epibatidine binding.
- Upregulation duration was drug- and region-specific: varenicline-induced upregulation was significantly longer lasting than nicotine in cortex, striatum, and hippocampus; overall upregulation remained significantly elevated up to 72 hr in cortex and striatum, while hippocampus and thalamus rapidly downregulated after treatment termination.
- Both drugs reduced marble burying, indicating anxiolytic-like effects. Nicotine’s effect was only observed during drug administration and absent 24 hr after cessation; varenicline’s effect was maintained up to 48 hr after cessation.
- Cortical [3H]EB binding was significantly correlated with marble-burying behavior in both nicotine and varenicline groups across all timepoints, with higher nAChR levels corresponding to fewer marbles buried. No significant correlation was observed for striatum, hippocampus, or thalamus.
Methods
- Male 129SvJ;C57Bl/6J F1 hybrid mice (6–12 weeks, 25–35 g) were group housed and randomly assigned to treatment. Nicotine tartrate, varenicline tartrate, or saline was infused subcutaneously via osmotic minipumps for 14 days; withdrawal was induced by pump removal at 24 hr, 48 hr, 72 hr, or 7 days before testing.
- Marble-burying test: mice (n = 6 per group) were placed individually in cages with 20 marbles on bedding for 15 min; a blind observer counted marbles buried by three quarters or more.
- Receptor binding: brain tissues were homogenized and incubated with 2 nM [3H]epibatidine; nonspecific binding was determined with 300 μM nicotine. Data were analyzed with two-way ANOVA followed by Bonferroni’s multiple comparison tests and Pearson correlation with 95% CI.
Limitations
- The paper states that the marble-burying test may not directly correlate with other tests of anxiety (open-field and light–dark box) and may more accurately reflect perseverative behavior; it also notes that no anxiogenic withdrawal effect was apparent in this test.
- The paper states that determining whether nAChR upregulation and anxiolytic-like responses are causally related will be important; causality was not established.
- Evident from the text: only male mice were used, with n = 6 per group, and only single chronic doses of nicotine and varenicline were tested; no female or human data are reported.
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- Findingown data§ Results
No significant correlation was observed between the density of nicotinic receptors in the striatum, hippocampus, or thalamus and the number of marbles buried.
“No significant correlation was observed between the density of nicotinic receptors in the striatum, hippocampus, or thalamus with the number of marbles buried”
Quote in the paperNot a substantial claim - Findingown data§ Results
In the cortex, [3H]EB binding was significantly correlated with marble-burying behavior in both the nicotine and varenicline treatment groups across all timepoints, with higher nAChR levels corresponding to fewer marbles buried.
“in the cortex, [3H]EB binding was significantly correlated with marble-burying behavior in both the nicotine and the varenicline treatment groups across all timepoints, where higher levels of nAChRs corresponded to fewer marbles buried”
- Also stated in: § Discussion · boosted
“The present data demonstrate a striking temporal correlation between nAChR upregulation and anxiolytic-like response to chronic nicotine and varenicline.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Findingown data§ Results
The duration of nAChR upregulation following cessation of treatment was drug-specific: varenicline-induced upregulation was significantly longer lasting than nicotine-induced upregulation in the cortex, striatum, and hippocampus.
“Drug-specific effects were observed in the cortex (A), striatum (B), and hippocampus (C), where the upregulation induced by varenicline treatment was significantly longer lasting compared with chronic nicotine treatment.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
No anxiogenic withdrawal effect was apparent in the marble-burying test following cessation of chronic nicotine or varenicline.
“no anxiogenic withdrawal effect was apparent in the marble-burying test.”
Quote in the paperSubstantial claim - Findingown data§ Results
In varenicline-treated animals, the anxiolytic-like effect in the marble-burying test was observed up to 48 hr following cessation of treatment.
“in varenicline-treated animals, an anxiolytic-like effect was observed up to 48 hr following cessation of treatment.”
Quote in the paperSubstantial claim
- Findingown data§ Results
Chronic administration of both nicotine (18 mg/kg/day) and varenicline (1.8 mg/kg/day) reduced the number of marbles buried in the marble-burying test, indicating an anxiolytic-like response.
“both chronic nicotine (18 mg/kg/day) and chronic varenicline (1.8 mg/kg/day) resulted in a reduced number of marbles being buried, indicating an anxiolytic-like response.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
Regulation of the α4β2 nAChR subtype may underlie the affective effects of both nicotine and varenicline.
“Thus, regulation of this subtype may underlie the affective effects of both nicotine and varenicline.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
Receptor upregulation is suggested as a mechanism for varenicline's efficacy as a smoking cessation therapy.
“These findings suggest receptor upregulation as a mechanism for its efficacy as a smoking cessation therapy.”
Quote in the paperSubstantial claim- Rests on an assumption: Anxiolytic-like responses measured by marble-burying behavior in mice are a valid model of the affective symptoms relevant to human smoking cessation and relapse.
- Premisecitation§ Introduction
Chronic administration of nicotine results in robust upregulation of receptors, predominantly the α4β2* nAChR subtype.
“Chronic administration of nicotine results in a robust upregulation of receptors, predominantly the α4β2* nAChR subtype”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Flores, Rogers, Pabreza, Wolfe, & Kellar, 1992
Not checked in the free run.
- Premisecitation§ Discussion
α4* or β2* knockout mice do not express anxiogenic phenotypes following nicotine withdrawal.
“α4* or β2* knockout mice do not express anxiogenic phenotypes following nicotine withdrawal”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fowler et al., 2008 source
Not checked in the free run.
- Premisecitation§ Discussion
The Ki of varenicline for α4β2 nAChRs (0.4 nM) is approximately 10 times higher than that of nicotine (6.0 nM).
“The Ki of varenicline for α4β2 nAChRs (0.4 nM) is ∼10× higher than that of nicotine (6.0 nM”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rollema, Hajos, et al., 2009
Not checked in the free run.
- Premisecitation§ Discussion
Nicotine is rapidly metabolized, resulting in a very short half-life in the mouse of 6-7 min.
“nicotine is rapidly metabolized, resulting in a very short half-life in the mouse of 6–7 min”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Matta et al., 2007 source
Not checked in the free run.
- Premisecitation§ Discussion
The marble-burying test has been shown to be responsive to clinically relevant medications for anxiety disorders, including anxiolytics such as chlordiazepoxide and antidepressants such as fluoxetine.
“the marble-burying test has been shown to be responsive to clinically relevant medications for anxiety disorders, both anxiolytics such as chlordiazepoxide and antidepressants such as fluoxetine”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Broekkamp et al., 1986
Not checked in the free run.
- cites Ichimaru et al., 1995 source
Not checked in the free run.
- cites Njung’e & Handley, 1991
Not checked in the free run.
- The quote only partly states this claim. 1
- May combine two claims. 8
- Classified as probably not a substantial claim. 4
The quote only partly states this claim.
Findingown data§ AbstractChronic administration of nicotine (18 mg/kg/day, free base) and varenicline (1.8 mg/kg/day) for 14 days significantly upregulated heteromeric nAChRs in the cortex, hippocampus, striatum, and thalamus of mice.
“We found that both nicotine (18 mg/kg/day, free base) and varenicline (1.8 mg/kg/day) chronically administered for 14 days upregulated nAChRs significantly in the cortex, hippocampus, striatum, and thalamus.”
- Also stated in: § Results · plain
“both chronic nicotine (18 mg/kg/day, free base) and chronic varenicline (1.8 mg/kg/day) administration resulted in significant upregulation of nAChRs in the cortex, striatum, hippocampus, and thalamus.”
Quote in the paperSubstantial claim- Also stated in: § Results · plain
May combine two claims.
Findingown data§ ResultsThe duration of nAChR upregulation following cessation of treatment was region-specific: upregulation remained significantly elevated for up to 72 hr in the cortex and striatum, while the hippocampus and thalamus rapidly downregulated nAChRs following termination of treatment.
“Overall upregulation of nAChRs following cessation of treatment remained significantly elevated for up to 72 hr in the cortex (A) and striatum (B), while the hippocampus (C) and thalamus (D) rapidly downregulated nAChRs following termination of treatment.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsIn nicotine-treated animals, the anxiolytic-like effect in the marble-burying test was observed only during drug administration, and behavior returned to baseline by 24 hr after cessation.
“In nicotine-treated animals, this effect was only observed during drug administration and behavior returned to baseline by 24 hr.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Premisenone given§ AbstractVarenicline is an efficacious smoking cessation aid, with a proposed mechanism of action that includes modulation of dopamine release in reward areas of the brain.
“Varenicline has been shown to be an efficacious smoking cessation aid, with a proposed mechanism of action that includes modulation of dopamine release in reward areas of the brain.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given§ Materials and methodsAnimals were randomly assigned to treatment conditions and tested in counterbalanced order.
“with animals randomly assigned to treatment conditions and tested in counterbalanced order”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ Materials and methodsThe number of buried marbles was counted by a blind observer.
“a blind observer counted the number of buried marbles”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ DiscussionThe cortex may play a role in mediating marble-burying behavior, though the correlation may also reflect a difference in nAChR subtypes within this brain region.
“While the cortex may play a role in mediating marble-burying behavior, this correlation may also reflect a difference in nAChR subtypes within this brain region.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown data§ ResultsThe experimental design allowed behaviors in the marble-burying test to be directly correlated with nAChR levels as evaluated by [3H]EB binding.
“One strength of the experimental design was the ability to directly correlate behaviors observed in the marble-burying test with nAChR levels as evaluated by [3H]EB binding.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ DiscussionHeteromeric nAChRs in the cortex are almost exclusively made up of the α4β2 subtype, which is the subtype most readily upregulated following chronic administration of nicotine.
“Heteromeric nAChRs in the cortex are almost exclusively made up of the α4β2 subtype, which is the subtype most readily upregulated following chronic administration of nicotine”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gaimarri et al., 2007 source
Not checked in the free run.
May combine two claims.
Premisecitation§ DiscussionVarenicline is not effectively metabolized and exhibits a relatively long half-life in the mouse of 1.4 hr.
“varenicline is not effectively metabolized and exhibits a relatively long half-life in the mouse of 1.4 hr”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Obach et al., 2006
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionVarenicline increases continuous abstinence rates to approximately 50% following 12 weeks of treatment, significantly better than bupropion (approximately 30%) or placebo (approximately 18%).
“Varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, is reported to increase continuous abstinence rates to ∼50% following 12 weeks of treatment, which is significantly better than bupropion (∼30%) or placebo (∼18%”
Quote in the paperNot a substantial claim0 of 3 sources checked
The paper relies on this without support.
Anxiolytic-like responses measured by marble-burying behavior in mice are a valid model of the affective symptoms relevant to human smoking cessation and relapse.
“These findings suggest receptor upregulation as a mechanism for its efficacy as a smoking cessation therapy.”
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?
The increased pool of nAChRs from chronic nicotine exposure may drive symptoms of nicotine withdrawal.
“The increased pool of nAChRs arising from chronic nicotine exposure may drive symptoms associated with the nicotine withdrawal syndrome (Turner et al. 2011; Gould et al. 2012)”
From Nicotine Withdrawal (2015) · cites this paper as Turner et al. 2011
The phenomenon of increased relapse rate following cessation of varenicline treatment may be related to varenicline's ability to induce nAChR upregulation.
“This phenomenon of increased relapse rate following cessation of varenicline treatment may be related to varenicline's ability to induce nAChR upregulation (Turner et al, 2011).”
From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Turner et al, 2011
Chronic administration of other nicotinic receptor ligands, including cytisine, anatoxin, and varenicline, up-regulates nAChRs in rodent brain.
“In addition to nicotine, chronic administration of other nicotinic receptor ligands up-regulate nAChRs in rodent brain, including cytisine (Schwartz and Kellar, 1985), anatoxin (Rowell and Wonnacott, 1990), and varenicline (Turner et al., 2011).”
From Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain (2012) · cites this paper as Turner et al., 2011
Nicotine upregulates nAChRs.
“As previously demonstrated, nicotine upregulates nAChRs, and receptors return to basal levels as early as 24 hour into withdrawal from nicotine (Fig. 3 and Turner et al., 2011).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Turner et al., 2011
Receptors return to basal levels as early as 24 hours into withdrawal from nicotine.
“As previously demonstrated, nicotine upregulates nAChRs, and receptors return to basal levels as early as 24 hour into withdrawal from nicotine (Fig. 3 and Turner et al., 2011).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Turner et al., 2011
Long-term exposure to varenicline upregulates nAChRs.
“Long-term exposure to varenicline upregulates nAChRs, which parallels its anxiolytic effects during cessation from nicotine (Turner et al., 2011).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Turner et al., 2011
The upregulated pool of nAChRs arising from long-term exposure to nicotine may drive elements of the nicotine withdrawal syndrome.
“Previous studies suggest that the upregulated pool of nAChRs arising from long-term exposure to nicotine may drive elements of the nicotine withdrawal syndrome (Turner et al., 2011;Gould et al., 2012), and this protracted upregulation of nAChRs has been correlated with reduced ability to maintain abstinence in the clinical population (Staley et al., 2006).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Turner et al., 2011
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.
Direction of cortical receptor-behavior correlation is contradictory
MinorThe abstract calls the correlation positive, but the Results state that higher cortical receptor levels corresponded to fewer marbles buried, which describes a negative correlation.
“Additionally, marble-burying behavior positively correlated to the regulation of cortical nAChRs following cessation of either treatment.”
“in the cortex, [3H]EB binding was significantly correlated with marble-burying behavior in both the nicotine and the varenicline treatment groups across all timepoints, where higher levels of nAChRs corresponded to fewer marbles buried (Figure 2B).”
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“The increased pool of nAChRs arising from chronic nicotine exposure may drive symptoms associated with the nicotine withdrawal syndrome (Turner et al. 2011; Gould et al. 2012) and might impact the ability to maintain abstinence in the clinical population (Staley et al. 2006).”
BackgroundCognitive function during nicotine withdrawal: Implications for nicotine dependence treatment
Ashare, R. L., Falcone, M., & Lerman, C. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.04.034 · Cited by 170 · see citing works
“For example, upregulation of nAChRs following chronic exposure has been demonstrated in rodents (Turner et al., 2011) and in post-mortem human brain (Breese et al., 1997).”
Govind, A. P., Walsh, H., & Green, W. N. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5438-11.2012 · Cited by 116 · see citing works
“Evidence of this is a recent study where radiolabeled agonist binding was assayed without delay and the fast decaying component of the upregulated binding was observed (Turner et al., 2011).”
BackgroundSex Differences in Smoking Cessation Pharmacotherapy Comparative Efficacy: A Network Meta-analysis
Smith, P. H., Weinberger, A. H., Zhang, J., Emme, E., Mazure, C. M., & McKee, S. A. (2016) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntw144 · Cited by 116 · see citing works
Discovery and development of varenicline for smoking cessation
Jordan, C. J., & Xi, Z. (2018) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2018.1458090 · Cited by 90 · see citing works
“upregulates nAchR binding in the cortex, hippocampus, thalamus, and striatum in mice [57,58].”
BackgroundEffects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice
AlSharari, S. D., King, J. R., Nordman, J. C., Muldoon, P. P., Jackson, A. B., Zhu, A. Z. X., Tyndale, R. F., Kabbani, N., & Damaj, M. I. (2015) · PLoS ONE · doi:10.1371/journal.pone.0137070 · Cited by 90 · see citing works
“Interestingly, temporal correlation between α4β2 nAChRs upregulation and nicotine withdrawal in rodents and humans were reported [23], [24].”
BackgroundDevelopmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning
Portugal, G. S., Wilkinson, D. S., Turner, J. R., Blendy, J. A., & Gould, T. J. (2012) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2012.04.003 · Cited by 79 · see citing works
Self-citationDetermining the pharmacokinetics of nicotinic drugs in the endoplasmic reticulum using biosensors
Shivange, A. V., Borden, P. M., Muthusamy, A. K., Nichols, A. L., Bera, K., Bao, H., Bishara, I., Jeon, J., Mulcahy, M. J., Cohen, B. N., et al. (2019) · The Journal of General Physiology · doi:10.1085/jgp.201812201 · Cited by 62 · see citing works
“Exposure to varenicline also up-regulates α4β2 nAChRs (Turner et al., 2011; Marks et al., 2015; Govind et al., 2017), an indication that it too participates in the inside-out pathway.”
Effects of chronic low- and high-dose nicotine on cognitive flexibility in C57BL/6J mice
Ortega, L. A., Tracy, B. A., Gould, T., & Parikh, V. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.10.032 · Cited by 67 · see citing works
Morphine dependence and withdrawal induced changes in cholinergic signaling
Neugebauer, N. M., Einstein, E. B., Lopez, M. B., McClure‐Begley, T. D., Mineur, Y. S., & Picciotto, M. R. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.04.015 · Cited by 53 · see citing works
“Upregulation of nAChRs has been observed following chronic treatment with nAChR agonists and partial agonists, such as nicotine and varenicline (Marks et al., 1983; Turner et al., 2011).”
BackgroundReward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice
Hilário, M. R. F., Turner, J. R., & Blendy, J. A. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.130 · Cited by 48 · see citing works
“Previously, nicotine receptor regulation was only determined after cessation of chronic nicotine treatment but not following repeated withdrawals (Collins et al, 1994; Hulihan-Giblin et al, 1990; Pietila et al, 1998; Turner et al, 2011).”
BackgroundMethodSelf-citationAnxiogenic-like effects of chronic nicotine exposure in zebrafish
Stewart, A., Grossman, L., Collier, A. D., Echevarria, D. J., & Kalueff, A. V. (2015) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2015.01.016 · Cited by 48 · see citing works
“Paralleling clinical findings, chronic administration induces consistent anxiogenic-like behavior in rodents treated with nicotine (Caldarone et al., 2008; Elliott et al., 2004; Mesa-Gresa et al., 2013) and some other nicotinic agonists (Turner et al., 2010) (see, however, (Turner et al., 2011)).”
Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence
Turner, J. R., Ray, R., Lee, B., Everett, L. J., Xiang, J. J., Jepson, C., Kaestner, K. H., Lerman, C. E., & Blendy, J. A. (2013) · Molecular Psychiatry · doi:10.1038/mp.2013.104 · Cited by 46 · see citing works
Self-citationActivation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal
Brynildsen, J. K., Lee, B. G., Perron, I. J., Jin, S., Kim, S. F., & Blendy, J. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1707047115 · Cited by 42 · see citing works
“Given the lack of studies on the effects of nicotine in nonsmokers, it is unclear whether nicotine reduces anxiety in the absence of withdrawal; however, numerous studies in rodent models have demonstrated dose-dependent anxiolytic effects of nicotine in drug-naïve subjects (5, 6).”
BackgroundMethodResultSelf-citationMolecular Mechanisms Associated with Nicotine Pharmacology and Dependence
Fowler, C. D., Turner, J. R., & Damaj, M. I. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_252 · Cited by 45 · see citing works
Self-citationChilds, E., Roche, D. J. O., King, A. C., & de Wit, H. (2012) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2011.01675.x · Cited by 45 · see citing works
“…any interactions between VAR and alcohol, which are mediated by changes in nicotinic receptor populations, that is, numbers or subunit composition, as a result of repeated dosing during pretreatment would not have been measured as this was outside the scope of this study (Turner et al., 2011).”
BackgroundAgboola, S., Coleman, T. J., McNeill, A. D., & Leonardi‐Bee, J. (2015) · Addiction · doi:10.1111/add.12941 · Cited by 37 · see citing works
Goldberg, L. R., Zeid, D., Kutlu, M. G., Cole, R. D., Lallai, V., Sebastian, A., Albert, I. U., Fowler, C. D., Parikh, V., & Gould, T. J. (2019) · Addiction Biology · doi:10.1111/adb.12859 · Cited by 38 · see citing works
Ashare, R. L., Tang, K. Z., Mesaros, A. C., Blair, I. A., Leone, F. T., & Strasser, A. A. (2012) · Journal of Psychopharmacology · doi:10.1177/0269881112449397 · Cited by 37 · see citing works
“Evidence that varenicline may have carryover effects (Patterson et al., 2009; Turner et al., 2011) prompted us to conduct post hoc tests to assess whether treatment order influenced cigarette consumption.”
BackgroundMethodSotomayor‐Zárate, R., Gysling, K., Busto, U. E., Cassels, B. K., Tampier, L., & Quintanilla, M. E. (2013) · Psychopharmacology · doi:10.1007/s00213-013-2974-3 · Cited by 36 · see citing works
“8 mg/kg/day for 14 days also induced upregulation of nicotinic receptors (Turner et al. 2011) in rat brain.”
InfluentialHussmann, 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., et al. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.198085 · Cited by 34 · see citing works
“Furthermore, in preclinical tests these doses of saz-A produce behaviors that are consistent with potential antidepressant and/or antianxiety effects (Kozikowski et al., 2009; Turner et al., 2010, 2011; Caldarone et al., 2011).”
InfluentialSelf-citationFisher, M. L., LeMalefant, R., Zhou, L., Huang, G., & Turner, J. R. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.257 · Cited by 31 · see citing works
“This dose, reported as freebase weight and based on previous work (Turner et al, 2010, 2011, 2013, 2014), corresponds to plasma levels of ~0.3 μM following chronic treatment for 12 days (Matta et al, 2007), a concentration similar to that observed in human smokers consuming an average of 17…”
MethodInfluentialSelf-citationWilkinson, D. S., Turner, J. R., Blendy, J. A., & Gould, T. J. (2013) · Psychopharmacology · doi:10.1007/s00213-012-2808-8 · Cited by 32 · see citing works
“Dose reported as freebase weight and based off of previous work (Turner et al. 2011a).”
Self-citationFasoli, F., Moretti, M., Zoli, M., Pistillo, F., Crespi, A., Clementi, F., McClure‐Begley, T. D., Marks, M. J., & Gotti, C. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.04.048 · Cited by 33 · see citing works
Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal
Turner, J. R., Wilkinson, D. S., Poole, R. L., Gould, T. J., Carlson, G. C., & Blendy, J. A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.105 · Cited by 29 · see citing works
Self-citationYohn, N. L., Turner, J. R., & Blendy, J. A. (2014) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.211706 · Cited by 28 · see citing works
“Chronic exposure to varenicline upregulates nAChRs, which parallels its anxiolytic effects during cessation from nicotine (Turner et al., 2011).”
BackgroundInfluentialSelf-citationSanchez, V., Carpenter, M. D., Yohn, N. L., & Blendy, J. A. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4425-4 · Cited by 28 · see citing works
“The marble burying test was performed as previously described (Turner et al. 2011).”
MethodSelf-citationNichols, A. L., Blumenfeld, Z., Fan, C., Luebbert, L., Blom, A. E. M., Cohen, B. N., Marvin, J. S., Borden, P. M., Kim, C. H., Muthusamy, A. K., et al. (2022) · eLife · doi:10.7554/elife.74648 · Cited by 25 · see citing works
Thyroid hormone signaling: Contribution to neural function, cognition, and relationship to nicotine
Leach, P. T., & Gould, T. J. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.09.001 · Cited by 24 · see citing works
Fox-Loe, A. M., Moonschi, F. H., & Richards, C. I. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.661827 · Cited by 27 · see citing works
“These drugs include the partial agonists cytisine (19) and varenicline (20) as well as the antagonist mecamylamine (21).”
Backgroundα4β2 * Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait–Balance Disorders
Albin, R. L., Müller, M. L. T. M., Bohnen, N. I., Spino, C., Sarter, M. F., Koeppe, R. A., Szpara, A., Kim, K., Lustig, C., & Dauer, W. T. (2021) · Annals of Neurology · doi:10.1002/ana.26102 · Cited by 30 · see citing works
“α4β2 nAChR agonists may induce nAChR expression, and it is possible that receptor density may not be stable during α4β2 nAChR agonist exposure.(26) As we”
BackgroundLotfipour, S., Mandelkern, M. A., Alvarez-Estrada, M., & Brody, A. L. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.20 · Cited by 26 · see citing works
“Indeed, preclinical evidence demonstrates that chronic varenicline treatment can increase the density of a4b2* nAChRs after a 2-week administration (with behavioral correlates), similar to the effects of chronic nicotine exposure over the same time period (Turner et al, 2011).”
BackgroundLange‐Asschenfeldt, C., Schäble, S., Suvorava, T., Gholamreza-Fahimi, E., Bisha, M., Stermann, T., Henning, U., & Kojda, G. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.03.025 · Cited by 26 · see citing works
Dissociation of tolerance and nicotine withdrawal-associated deficits in contextual fear
Gould, T. J., Wilkinson, D. S., Yildirim, E., Blendy, J. A., & Adoff, M. D. (2014) · Brain Research · doi:10.1016/j.brainres.2014.02.038 · Cited by 25 · see citing works
“Binding data were expressed as fmol/mg tissue (Turner et al., 2010, 2011).”
MethodSelf-citationHayase, T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0158950 · Cited by 25 · see citing works
Hussmann, G. P., DeDominicis, K. E., Turner, J. R., Yasuda, R. P., Klehm, J., Forcelli, P. A., Xiao, Y., Richardson, J. R., Sahibzada, N., Wolfe, B. B., et al. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12653 · Cited by 23 · see citing works
“Nicotine, varenicline, and saz-A have been reported to produce effects consistent with anxiolytic and/or antidepressant activity in rodents (Patterson et al. 2009; Kozikowski et al. 2009; Turner et al. 2010, 2011).”
InfluentialSelf-citationGowin, J. L., Vatsalya, V., Westman, J. G., Schwandt, M. L., Bartlett, S. E., Heilig, M. A., Momenan, R., & Ramchandani, V. A. (2016) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.13046 · Cited by 22 · see citing works
“This suggests that varenicline affects neural correlates associated with processing negative emotionality in smokers, which corroborates evidence that directly stimulating nAChRs can reduce anxiety in both animals and humans (Elliott et al., 2004; Kassel and Shiffman, 1997; Turner et al., 2011).”
BackgroundKoul, S., Schaal, V. L., Chand, S., Pittenger, S. T., Vellichirammal, N. N., Kumar, V., Guda, C., Bevins, R. A., Yelamanchili, S. V., & Pendyala, G. (2020) · Cells · doi:10.3390/cells9081883 · Cited by 23 · see citing works
“Previously published research has established that cyclins are associated with nicotine addiction [70].”
BackgroundChronic treatment with varenicline changes expression of four nAChR binding sites in mice
Marks, M. J., O’Neill, H. C., Wynalda, K., Ortiz, N. C., Simmons, E. E., Short, C. A., Butt, C. M., McIntosh, J. M., & Grady, S. R. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.07.019 · Cited by 23 · see citing works
“The timecourse of reversal of this upregulation after cessation of treatment in mice is approximately a week in mice (Marks et al., 1985; Turner et al., 2011; Yohn et al., 2014).”
Govind, A. P., Vallejo, Y. F., Stolz, J. R., Yan, J.-Z., Swanson, G. T., & Green, W. N. (2017) · eLife · doi:10.7554/elife.25651 · Cited by 17 · see citing works
“DOI: 10.7554/eLife.25651 2 of 23 (Hussmann et al., 2012; Turner et al., 2011).”
BackgroundInfluentialDuBois, D. W., Damborsky, J. C., Fincher, A. S., Frye, G. D., & Winzer‐Serhan, U. H. (2013) · Life Sciences · doi:10.1016/j.lfs.2012.12.013 · Cited by 19 · see citing works
Molecular, Neuronal, and Behavioral Effects of Ethanol and Nicotine Interactions
Klenowski, P. M., & Tapper, A. R. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2017_89 · Cited by 15 · see citing works
Hussmann, G. P., Yasuda, R. P., Xiao, Y., Wolfe, B. B., & Kellar, K. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.289546 · Cited by 15 · see citing works
Varani, A. P., Moutinho, L. M., & Balerio, G. N. (2014) · Synapse · doi:10.1002/syn.21763 · Cited by 16 · see citing works
“Interestingly, an increase of striatal nAChRs density has been observed after cessation of chronic NIC treatment (Slotkin et al., 2007; Turner et al., 2011).”
BackgroundCole, R. D., Wolsh, C. C., Zimmerman, M., Harrington, E. N., Gould, T. J., & Parikh, V. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.07.019 · Cited by 15 · see citing works
Sex-specific transgenerational effects of morphine exposure on reward and affective behaviors
Brynildsen, J. K., Sanchez, V., Yohn, N. L., Carpenter, M. D., & Blendy, J. A. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112842 · Cited by 14 · see citing works
“Marble burying The marble burying test was performed in F1 and F2 mice (n = 12-28/group) as previously described [15].”
MethodSelf-citationFarías-Cea, A., Leal, C., Hödar-Salazar, M., Esparza, E., Martinez-Duran, L. M., Fuentes, I., & Iturriaga‐Vásquez, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310635 · Cited by 16 · see citing works
Abreu‐Villaça, Y., Correa‐Santos, M., Dutra-Tavares, A. C., Paes‐Branco, D., Nunes‐Freitas, A. L., Manhães, A. C., Filgueiras, C. C., & Ribeiro‐Carvalho, A. (2016) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2016.06.002 · Cited by 15 · see citing works
“…shown in animal models of nicotine exposure (Abreu-Villaç a et al., 2003; RibeiroCarvalho et al., 2009; Trauth et al., 1999), nAChR binding tends to return to baseline levels within days in rodent models (RibeiroCarvalho et al., 2009; Turner et al., 2011) or weeks in humans (Mamede et al., 2007).”
Effects of nicotine and stress exposure across generations in C57BL/6 mice
Yohn, N. L., Caruso, M. J., & Blendy, J. A. (2019) · Stress · doi:10.1080/10253890.2018.1532991 · Cited by 13 · see citing works
Self-citationFox-Loe, A. M., Moonschi, F. H., & Richards, C. I. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.801431 · Cited by 11 · see citing works
Predicted Impact of Nicotine Reduction on Smokers with Affective Disorders
Gaalema, D. E., Miller, M. E., & Tidey, J. W. (2015) · Tobacco Regulatory Science · doi:10.18001/trs.1.2.5 · Cited by 13 · see citing works
Rezvani, A. H., Timofeeva, O., Sexton, H. G., DeCuir, D., Xiao, Y., Gordon, C. J., Kellar, K. J., & Levin, E. D. (2012) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.02.031 · Cited by 13 · see citing works
“…effects (Cucchiaro et al., 2008); reduction of nicotine and alcohol self-administration (Levin et al., 2010; Rezvani et al., 2010), and induction of behaviors consistent with anxiolytic and possibly antidepressant effects (Caldarone et al., 2011; Kozikowski et al., 2009; Turner et al., 2011).”
Lee, B. G., Anastasía, A., Hempstead, B. L., Lee, F. S., & Blendy, J. A. (2015) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntv047 · Cited by 13 · see citing works
Self-citationZaccarelli‐Magalhães, J., Sandini, T. M., Abreu, G., Petrocelli, B. M., Moreira, N. C. D. S., Reis-Silva, T. M., Lebrun, I., Flório, J. C., Ricci, E. L., Fukushima, A. R., et al. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.03.009 · Cited by 12 · see citing works
Lee, A. M., Arreola, A. C., Kimmey, B. A., & Schmidt, H. D. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.08.016 · Cited by 13 · see citing works
“This limited therapeutic benefit may be due, in part, to increased expression of β2-containing nAChRs in the brain [11].”
BackgroundForcelli, P. A., Turner, J. R., Lee, B. G., Olson, T. T., Xie, T., Xiao, Y., Blendy, J. A., & Kellar, K. J. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.09.012 · Cited by 11 · see citing works
“(FST; Mice) The FST in mice was conducted as previously described (Turner et al., 2011).”
BackgroundMethodInfluentialSelf-citationLeach, P. T., Holliday, E. D., Kutlu, M. G., & Gould, T. J. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntu229 · Cited by 12 · see citing works
Keady, J. V., Hessing, M. C., Songrady, J. C., McLaurin, K. A., & Turner, J. R. (2024) · Biology of Sex Differences · doi:10.1186/s13293-024-00656-6 · Cited by 9 · see citing works
“This dose is based on previous work [58, 62–64] and corresponds to plasma levels of ∼ 0.3 µM [65], a concentration similar to that observed in human smokers consuming an average of 17 cigarettes a day (plasma levels between 0.06 and 0.31 µM) [65].”
MethodInfluentialSelf-citationVarani, A. P., Antonelli, M. C., & Balerio, G. N. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.02.016 · Cited by 7 · see citing works
Dynamic Effects of Ventral Hippocampal NRG3/ERBB4 Signaling on Nicotine Withdrawal-Induced Responses
Fisher, M. L., Prantzalos, E. R., O’Donovan, B., Anderson, T. L., Sahoo, P. K., Twiss, J. L., Ortinski, P. I., & Turner, J. R. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109846 · Cited by 6 · see citing works
Self-citationAge‐specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling
Keady, J. V., Fisher, M. L., Anderson, E., LeMalefant, R., & Turner, J. R. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15780 · Cited by 6 · see citing works
“This dose, reported as freebase weight and based off of previous work (Turner et al., 2010, 2011, 2013, 2014), corresponds to plasma levels of 0.3 μM (Matta et al., 2007), a concentration similar to that observed in human smokers consuming an average of 17 cigarettes a day (plasma levels between…”
ResultInfluentialSelf-citationVarenicline disrupts prepulse inhibition only in high-inhibitory rats
Göktalay, T., Buyukuysal, S., Uslu, G., Coşkun, A. Ş., Yorgancıoğlu, A., Kayır, H., Uzbay, T. I., & Göktalay, G. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.03.001 · Cited by 5 · see citing works
“Thus, although some studies reported that varenicline had antidepressant (Rollema et al., 2009a), anxiolytic (Turner et al., 2011) and analgesic (AlSharari et al., 2012) effects in several animal models, it may disrupt sensorimotor gating, at least in a sub-group of animals.”
Fox-Loe, A. M., Dwoskin, L. P., & Richards, C. I. (2016) · Neuromethods · doi:10.1007/978-1-4939-3768-4_7 · Cited by 5 · see citing works
“, mecamylamine) also upregulate some subtypes of nAChRs [21, 30, 32], including those composed of α4 and β2 subunits.”
BackgroundNeed for medication to complement catecholamines in smoking cessation of hardcore smokers
Kawai, A., Kurita, M., Nishino, S., Hirata, E., Sato, T., & Okubo, Y. (2017) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s144181 · Cited by 5 · see citing works
“11 Dopaminergic mechanisms have been implicated in both the reward aspects of nicotine and in the manifestations of nicotine withdrawal syndrome.”
α4β2 nicotinic acetylcholine receptors intrinsically influence body weight in mice
Dezfuli, G., Olson, T. T., Martin, L. M., Keum, Y., Siegars, B., Desai, A., Uitz, M., Sahibzada, N., Gillis, R. A., & Kellar, K. J. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107921 · Cited by 5 · see citing works
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Theng, Y. M., Wahab, S. B., Wahab, N. A. A., Sidi, H., & Das, S. (2017) · Current Drug Targets · doi:10.2174/1389450118666171017163741 · Cited by 3 · see citing works
Varani, A. P., Pedrón, V. T., Aon, A. J., Canero, E., & Balerio, G. N. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111786 · Cited by 3 · see citing works
Pross, B., Muenz, S., Nitsche, M. A., et al. (2023) · Brain Research · doi:10.1016/j.brainres.2023.148380 · Cited by 2 · see citing works
Chapter 18. Neurobiology of Nicotine and Tobacco
Gubner, N. R., & Benowitz, N. L. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb18 · Cited by 2 · see citing works
Nichols, A. L., Blumenfeld, Z., Fan, C., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.04.463082 · Cited by 2 · see citing works
Umene‐Nakano, W., Yoshimura, R., Hori, H., Katsuki, A., Hayashi, K., Yoshii, C., Ikenouchi, A., Atake, K., & Nakamura, J. (2012) · Open Journal of Psychiatry · doi:10.4236/ojpsych.2012.224046 · Cited by 1 · see citing works
“[31] have reported that varenicline has been shown to be an efficacious smoking cessation aid, with a proposed mechanism of action that includes the modulation of dopamine release in reward areas of the brain.”
BackgroundBashkatova, V. G., Sudakov, S. K., Nazarova, G. A., et al. (2014) · Pharmacology & Pharmacy · doi:10.4236/pp.2014.511117 · Cited by 1 · see citing works
“Nicotine has been shown to affect anxiety and depression in both human and animal studies [20]-[22].”
BackgroundDynamic Effects of Ventral Hippocampal NRG3/ERBB4 Signaling on Nicotine Withdrawal-Induced ResponsesPreprint
Fisher, M. L., Prantzalos, E. R., O’Donovan, B., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.17.524432 · Cited by 1 · see citing works
Self-citationPharmakologische und nicht-pharmakologische Effekte auf die Kognition
Both, C. (2013) · Univ. Duesseldorf: Duesseldorfer Dokumenten- und Publikationsserver
Enhancing the efficacy of a nicotine vaccine
Cornish, K. E. (2013) · University of Minnesota Digital Conservancy (University of Minnesota)
Fox-Loe, A. M. (2016) · UKnowledge (University of Kentucky) · doi:10.13023/etd.2016.461
“Cytisine and varenicline, both partial agonists of α4β2, have previously been shown to increase the number of α4β2 nAChRs on the plasma membrane [176, 178, 210, 238, 258].”
BackgroundInfluentialDadashova, R. (2011) · ERA: Education and Research Archive (University of Alberta) · doi:10.7939/r3xh8f
α4β2 * Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance DisordersPreprint
Albin, R. L., Müller, M. L. T. M., Bohnen, N. I., et al. (2020) · medRxiv · doi:10.1101/2020.10.11.20210914
Regulation of Neuronal Nicotinic Receptor Expression by Novel Ligands and Mechanisms
Hussmann, G. P. (2012) · DigitalGeorgetown (Georgetown University Library)
- Authors
- Turner, J. R., Castellano, L. M., & Blendy, J. A.
- Affiliations
- University of Pennsylvania (US)
- Venue
- Nicotine & Tobacco Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-11-22
- Volume
- 13
- Issue
- 1
- Pages
- 41-46
- ISSN
- 1462-2203 (ISSN-L)
- 1469-994X
- PMC
- PMC3001959
- OpenAlex
- W2160083250
- Semantic Scholar
- 577dce229e013de39a97a18a1de3b2a6830aabfe
- Cited by
- 78
- References
- 41
- Citations by year
- 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 10 · 2015: 10 · 2014: 8 · 2013: 9 · 2012: 13
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nicotine & Tobacco Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Pfizer
- National Institute on Drug Abuse (F32DA026236, 1-F32-DA026236-01A1)
- National Cancer Institute (P50CA143187)
- 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, varenicline, nicotine, receptor up-regulation, anxiolytic effects, marble burying test, smoking cessation, epibatidine binding, withdrawal symptoms, dopamine release
- MeSH terms
- Varenicline, Animals, Benzazepines, Cerebral Cortex, Hippocampus, Male, Nicotine, Quinoxalines, Receptors, Nicotinic, Substance Withdrawal Syndrome, Thalamus, Up-Regulation, Smoking Cessation, Mice
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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.
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