Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum
Open accessAbstract
Extensive evidence indicates that varenicline reduces nicotine craving and withdrawal symptoms by modulating dopaminergic function at α4β2* nicotinic acetylcholine receptors (nAChRs) (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex). More recent data suggest that α6β2* nAChRs also regulate dopamine release and mediate nicotine reinforcement. The present experiments were therefore done to test the effect of varenicline on α6β2* nAChRs and their function, because its interaction with this subtype is currently unclear. Receptor competition studies showed that varenicline inhibited α6β2* nAChR binding (K(i) = 0.12 nM) as potently as α4β2* nAChR binding (K(i) = 0.14 nM) in rat striatal sections and with ∼20-fold greater affinity than nicotine. Functionally, varenicline was more potent in stimulating α6β2* versus α4β2* nAChR-mediated [(3)H]dopamine release from rat striatal synaptosomes with EC(50) values of 0.007 and 0.086 μM, respectively. However, it acted as a partial agonist on α6β2* and α4β2* nAChR-mediated [(3)H]dopamine release with maximal efficacies of 49 and 24%, respectively, compared with nicotine. We also evaluated varenicline's action in striatum of monkeys, a useful animal model for comparison with humans. Varenicline again potently inhibited monkey striatal α6β2* (K(i) = 0.13 nM) and α4β2* (K(i) = 0.19 nM) nAChRs in competition studies. Functionally, it potently stimulated both α6β2* (EC(50) = 0.014 μM) and α4β2* (EC(50) = 0.029 μM) nAChR-mediated [(3)H]dopamine release from monkey striatal synaptosomes, again acting as a partial agonist relative to nicotine at both subtypes. These data suggest that the ability of varenicline to interact at α6β2* nAChRs may contribute to its efficacy as a smoking cessation aid.
AI snapshot
Written from the paper’s full text.
TL;DR
Varenicline binds with high affinity to both α6β2* and α4β2* nicotinic acetylcholine receptors (nAChRs) in rat and monkey striatum and acts as a potent partial agonist at α6β2* nAChRs to stimulate dopamine release. These data suggest that varenicline’s interaction at α6β2* nAChRs may contribute to its efficacy as a smoking cessation aid.
Key findings
- In rat striatum, varenicline inhibited α6β2* nAChR binding with Ki = 0.12 ± 0.02 nM and α4β2* nAChR binding with Ki = 0.14 ± 0.01 nM, making it about 20-fold more potent than nicotine (Ki = 1.68 ± 0.15 nM and 3.77 ± 0.76 nM, respectively).
- In monkey striatum, varenicline inhibited α6β2* nAChRs with Ki = 0.13 ± 0.01 nM and α4β2* nAChRs with Ki = 0.19 ± 0.11 nM, about 6-fold more potent than nicotine (Ki = 0.61 ± 0.09 nM and 1.43 ± 0.24 nM, respectively).
- Functionally, varenicline was a partial agonist at both subtypes: in rat, maximal α6β2* nAChR-mediated [3H]dopamine release was 49% of nicotine’s and α4β2* release was 24%; in monkey, maximal α6β2* release was 13% and α4β2* release was 42% of nicotine’s.
- Varenicline was more potent than nicotine in stimulating release: rat EC50 values were 0.007 M at α6β2* and 0.086 M at α4β2* (nicotine: 0.19 and 5.42 M); monkey EC50 values were 0.014 M at α6β2* and 0.029 M at α4β2* (nicotine: 0.68 and 1.21 M).
Methods
- Receptor autoradiography in rat and monkey striatal sections: [125I]α-conotoxin MII for α6β2* nAChRs and [125I]epibatidine in the presence of α-CtxMII for α4β2* nAChRs, with competition curves for varenicline and nicotine.
- [3H]dopamine release from rat and monkey striatal synaptosomes, using α-CtxMII to distinguish α6β2* and α4β2* nAChR-mediated components; dose-response curves analyzed by nonlinear regression.
- Animals: male Sprague-Dawley rats (200–250 g) and squirrel monkeys (600–1050 g); binding data from 8 rats or 3 monkeys, release data from 4–8 rats or 3 monkeys.
Limitations
- The paper does not state a formal limitations section. It notes that the current results are from acute experiments, and it discusses chronic varenicline exposure and desensitization as a possible long-term mechanism rather than testing it here.
- Evident from the text: the study uses in vitro autoradiography and synaptosomal dopamine release, so it does not directly measure in vivo behavioral, reinforcement, or clinical smoking-cessation outcomes.
- Evident from the text: monkey experiments used a small sample (n = 3), and the conclusion that α6β2* interaction contributes to varenicline’s efficacy is framed as a suggestion (“may contribute”) rather than a demonstrated clinical mechanism.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 44 cited sources checked · 0 supported · 0 flagged
- Findingown data
Total varenicline-evoked dopamine release from monkey striatal synaptosomes is about 80% lower than nicotine-evoked release.
“Total varenicline-evoked [ 3 H]dopamine release in monkey striatum was ϳ80% lower than that evoked by nicotine”
Quote in the paperSubstantial claim - Findingown data
Total varenicline-evoked dopamine release from rat striatal synaptosomes is about 60% lower than nicotine-evoked release.
“The results (Fig. 2) show that total varenicline-evoked [ 3 H]dopamine release was ϳ60% lower than that evoked by nicotine”
Quote in the paperSubstantial claim - Findingown data
In rat striatal sections, varenicline inhibits α6β2* nAChR binding with a Ki of 0.12 nM.
“Receptor competition studies showed that varenicline inhibited ␣62* nAChR binding (K i ϭ 0.12 nM) as potently as ␣42* nAChR binding (K i ϭ 0.14 nM) in rat striatal sections”
- Also stated in: § Results · plain
“Competition analyses of [ 125 I]␣-CtxMII binding at varying concentrations of varenicline (10 Ϫ12 to 10 Ϫ7 M) showed that varenicline potently inhibited ␣62* nAChR binding with a K i value of 0.12 Ϯ 0.02 nM”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
Varenicline is about 20-fold more potent than nicotine at α6β2* and α4β2* nAChRs in rat striatum.
“Thus varenicline is approximately 20 times more potent than nicotine at ␣62* and ␣42* nAChRs in rat striatum.”
- Also stated in: § Abstract · plain
“with ϳ20-fold greater affinity than nicotine”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
In rat striatal sections, varenicline inhibits α4β2* nAChR binding with a Ki of 0.14 nM.
“as potently as ␣42* nAChR binding (K i ϭ 0.14 nM) in rat striatal sections”
- Also stated in: § Results · plain
“[ 125 I]epibatidine competition studies yielded a K i value of 0.14 Ϯ 0.01 nM, which was very similar to that for varenicline at ␣62* nAChRs”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
In monkey striatum, varenicline is about six times more potent than nicotine at α6β2* and α4β2* nAChRs in competition binding studies.
“Thus, varenicline is approximately six times more potent than nicotine at ␣62* and ␣42* nAChRs in competition binding studies in monkey striatum.”
Quote in the paperSubstantial claim - Findingown data
In monkey striatal sections, varenicline inhibits α4β2* nAChR binding with a Ki of 0.19 nM.
“and ␣42* (K i ϭ 0.19 nM) nAChRs in competition studies.”
- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
“The value for the total striatum was 0.19 Ϯ 0.11 nM”
Quote in the paperNot a substantial claim - Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
- Findingown data
In monkey striatal sections, varenicline inhibits α6β2* nAChR binding with a Ki of 0.13 nM.
“Varenicline again potently inhibited monkey striatal ␣62* (K i ϭ 0.13 nM)”
- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
“potently inhibited binding to ␣62* nAChRs in monkey striatal sections with a K i of 0.13 Ϯ 0.01 nM”
Quote in the paperSubstantial claim - Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
- Findingown data
In rat striatum, varenicline-evoked total [3H]dopamine release is only one-third of nicotine-evoked total release.
“However, varenicline-evoked total [ 3 H]dopamine release was only one-third of the total nicotine-evoked release”
Quote in the paperSubstantial claim - Findingown data
In monkey striatum, varenicline is much less efficacious than nicotine in stimulating [3H]dopamine release at both α6β2* and α4β2* nAChR subtypes.
“On the other hand, it was much less efficacious in stimulating [ 3 H]dopamine release compared with nicotine at both nAChR subtypes.”
Quote in the paperSubstantial claim - Findingcitation
In rat striatum, varenicline's binding affinity at α6β2* nAChRs is similar to that at α4β2* nAChRs.
“It is noteworthy that the binding affinity of varenicline for ␣62* nAChRs was very similar to that of ␣42* nAChRs, in agreement with Grady et al. (2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Grady et al., 2010 source
Not checked in the free run.
- Findingown data
Varenicline evokes striatal α6β2* nAChR-mediated [3H]dopamine release in rats.
“In addition, our data show that varenicline evoked striatal ␣62* nAChR-mediated [ 3 H]dopamine release”
Quote in the paperSubstantial claim - Findingown data
In rat striatum, varenicline binds to α6β2* nAChRs with about 20-fold higher affinity than nicotine.
“Our studies in rats showed that varenicline potently binds to ␣62* nAChRs with ϳ20-fold higher affinity than nicotine.”
Quote in the paperSubstantial claim - Findingown data
In rats, varenicline's potency at α6β2* nAChRs is greater than at α4β2* nAChRs.
“and its potency at the ␣62* nAChR was greater than at the ␣42* subtype.”
Quote in the paperSubstantial claim - Findingown data
In monkey striatum, varenicline stimulates [3H]dopamine release more potently than nicotine at α6β2* and α4β2* nAChR subtypes.
“The results also show that varenicline stimulated [ 3 H]dopamine release from monkey striatal synaptosomes more potently than nicotine at the ␣62* and ␣42* nAChR subtypes.”
Quote in the paperSubstantial claim - Findingown data
In monkey striatum, varenicline interacts with high affinity at both α6β2* and α4β2* nAChRs in receptor competition studies.
“The results are the first to show that varenicline interacts with high affinity at striatal ␣62* nAChRs and ␣42* nAChRs in receptor competition studies.”
Quote in the paperSubstantial claim - Findingown data
Varenicline potently interacts at α6β2* and α4β2* nAChRs in striatum.
“the present results show that varenicline potently interacts at ␣62* and ␣42* nAChRs in striatum”
Quote in the paperSubstantial claim - Findingown data
In monkey striatum, varenicline's Ki values at both α6β2* and α4β2* nAChRs are several times greater than those for nicotine.
“Moreover, varenicline's K i values at both subtypes is several times greater than that observed for nicotine, as in the rat.”
Quote in the paperNot a substantial claim - Findingown data
Varenicline binds with high affinity to α6β2* nAChRs in rat and monkey striatum.
“the present data demonstrate that varenicline binds with high affinity to ␣62* nAChRs in rat and monkey striatum.”
Quote in the paperSubstantial claim - Findingown data
Varenicline is a potent partial agonist in stimulating α6β2* nAChR-mediated dopamine release from striatal synaptosomes in both rat and monkey.
“They also show that varenicline is a potent partial agonist in stimulating ␣62* nAChR-mediated dopamine release from striatal synaptosomes in both animal models.”
Quote in the paperSubstantial claim - Findingown data
In monkey striatum, maximal varenicline-stimulated [3H]dopamine release at both α6β2* and α4β2* nAChRs is less than that evoked by nicotine.
“Both maximal ␣62* and ␣42* varenicline-stimulated [ 3 H]dopamine release were less than that evoked by nicotine”
Quote in the paperSubstantial claim - Findingown data
Varenicline is a partial agonist at monkey striatal α6β2* nAChRs.
“Varenicline is a partial agonist at monkey striatal ␣62* nAChRs.”
Quote in the paperSubstantial claim - Interpretationown data
Varenicline interacts with similar affinity at α6β2* and α4β2* nAChRs in rat striatum.
“These data indicate that varenicline interacts equally well with ␣62* and ␣42* nAChRs in rat striatum.”
Quote in the paperSubstantial claim - Premisecitation
α6β2* nAChR function is modified by nicotine exposure.
“Moreover, their function is modified by nicotine exposure”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Perez et al., 2008 source
Not checked in the free run.
- cites Perez et al., 2011
Not checked in the free run.
- Interpretationown data
Varenicline's interaction at α6β2* nAChRs may contribute to its effectiveness as a smoking cessation aid.
“These data suggest that the ability of varenicline to interact at ␣62* nAChRs may contribute to its efficacy as a smoking cessation aid.”
Quote in the paperSubstantial claim- Rests on an assumption: Monkeys serve as a valuable model for human comparison.
- Interpretationown data
Varenicline has similar potency at α4β2* and α6β2* nAChRs in monkey striatum.
“Thus, varenicline acts with a similar potency at ␣42* and ␣62* nAChRs in monkey striatum.”
Quote in the paperSubstantial claim - Interpretationown data
Varenicline may be a more potent partial agonist at α6β2* than at α4β2* nAChRs in rat striatum.
“Thus varenicline may be a more potent partial agonist at ␣62* than ␣42* nAChRs in rat striatum.”
Quote in the paperSubstantial claim - Premisecitation
Drugs that selectively inhibit α4β2* and/or α6β2* nAChRs block behaviors linked to nicotine reward and reinforcement when infused or given systemically.
“In addition, infusion and systemic administration of drugs that selectively inhibit ␣42* and/or ␣62* nAChRs blocked behaviors linked to nicotine reward and reinforcement”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Varenicline is a potent partial agonist at α6β2* nAChRs in the striatum of both rats and monkeys.
“The results show that varenicline is a potent partial agonist at ␣62* nAChRs in striatum of both rats and monkeys.”
Quote in the paperSubstantial claim - Premisecitation
The main nAChR subtypes in CNS dopaminergic systems that mediate nicotine's addictive effects are α4β2* and α6β2*.
“The primary nAChRs in CNS dopaminergic systems that mediate the addictive effects of nicotine are the ␣42* and ␣62* subtypes”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Barik and Wonnacott, 2009
Not checked in the free run.
- cites Changeux, 2010 source
Not checked in the free run.
- cites Mao and McGehee, 2010
Not checked in the free run.
- Premisecitation
α6β2* nAChRs have a critical and possibly dominant effect on dopaminergic neurotransmission in the mesolimbic and nigrostriatal dopaminergic system.
“Indeed, ␣62* nAChRs have been shown to have a critical and possibly dominant effect on dopaminergic neurotransmission in the mesolimbic and nigrostriatal dopaminergic system”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Nicotine and other nAChR agonists induce their behavioral effects via nAChR desensitization.
“This idea is consistent with an extensive literature suggesting that nicotine and other nAChR agonists induce their behavioral effects via this mechanism (Picciotto et al., 2008;Buccafusco et al., 2009;Bordia et al., 2010;Mineur and Picciotto, 2010;Grady et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Chronic varenicline exposure may lead to nAChR desensitization.
“With respect to a long-term mechanism of action, chronic varenicline exposure may subsequently lead to nAChR desensitization (Ortiz et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ortiz et al., 2012 source
Not checked in the free run.
- Interpretationreasoning
The mode of interaction of varenicline at α6β2* nAChRs is similar to that at α4β2* nAChRs.
“Thus the mode of interaction of varenicline at ␣62* nAChRs is similar to that at ␣42* nAChRs, as shown here and reported by others (Grady et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Grady et al., 2010 source
Not checked in the free run.
- Interpretationown data
Varenicline acts as a partial agonist at nAChRs in rat striatum.
“supporting the idea that varenicline acts as a partial agonist.”
Quote in the paperSubstantial claim - Premisecitation
Varenicline activates expressed α6β2β3* nAChR concatamers at nanomolar concentrations (75-178 nM).
“Another series of studies in oocytes also showed that varenicline activated expressed ␣623* nAChR concatamers at nanomolar concentrations (75-178 nM)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kuryatov and Lindstrom, 2011
Not checked in the free run.
- Interpretationreasoning
The antismoking effects of varenicline may be caused by an interaction at both β2* nAChR populations.
“These data suggest that the antismoking effects of varenicline may be caused by an interaction at both 2* nAChR populations.”
Quote in the paperSubstantial claim - Interpretationown data
The results in monkeys corroborate those in rats regarding varenicline's interaction at α6β2* nAChRs.
“Thus, the results in monkeys corroborate those in the rat with respect to varenicline's ability to interact at ␣62* nAChRs.”
Quote in the paperSubstantial claim - Interpretationreasoning
Varenicline's action at α6β2* nAChRs may contribute to its efficacy as a smoking cessation aid.
“these observations may suggest that varenicline's action at ␣62* nAChRs contributes to its efficacy as a smoking cessation aid.”
Quote in the paperSubstantial claim0 of 2 sources checked
- May combine two claims. 15
- Classified as probably not a substantial claim. 8
May combine two claims.
Findingown dataIn rat striatal synaptosomes, varenicline stimulates α6β2* nAChR-mediated dopamine release more potently than α4β2* nAChR-mediated release, with EC50 values of 0.007 and 0.086 μM.
“Functionally, varenicline was more potent in stimulating ␣62* versus ␣42* nAChR-mediated [ 3 H]dopamine re-lease from rat striatal synaptosomes with EC 50 values of 0.007 and 0.086 M, respectively.”
- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
“The EC 50 values for vareniclinestimulated ␣62* and ␣42* nAChR-mediated release were 0.007 and 0.086 M, respectively (Table 3), compared with 0.19 and 5.42 M, respectively, for nicotine.”
Quote in the paperSubstantial claim- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
May combine two claims.
Findingown dataIn monkey striatal synaptosomes, varenicline acts as a partial agonist relative to nicotine at both α6β2* and α4β2* nAChRs.
“again acting as a partial agonist relative to nicotine at both subtypes.”
- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · hedged
“Thus varenicline also seems to be a potent partial agonist at ␣62* nAChRs in monkey striatum.”
Quote in the paperSubstantial claim- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · hedged
May combine two claims.
Findingown dataIn monkey striatal synaptosomes, varenicline stimulates α6β2* and α4β2* nAChR-mediated dopamine release with EC50 values of 0.014 and 0.029 μM, respectively.
“Functionally, it potently stimulated both ␣62* (EC 50 ϭ 0.014 M) and ␣42* (EC 50 ϭ 0.029 M) nAChR-mediated [ 3 H]dopamine release from monkey striatal synaptosomes”
- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
“Varenicline's EC 50 value for ␣62* nAChR-mediated release was 0.014 M, and for ␣42* nAChR-mediated release it was 0.029 M”
Quote in the paperSubstantial claim- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
May combine two claims.
Findingown dataIn rat striatal synaptosomes, varenicline is a partial agonist at α6β2* and α4β2* nAChRs, producing maximal dopamine release that is 49% and 24% of nicotine's effect, respectively.
“However, it acted as a partial agonist on ␣62* and ␣42* nAChR-mediated [ 3 H]dopamine release with maximal efficacies of 49 and 24%, respectively, compared with nicotine.”
- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
“Varenicline-evoked ␣62* nAChR-mediated [ 3 H]dopamine release was 49% of that evoked by nicotine, whereas release mediated via ␣42* nAChRs was 24% of nicotine-stimulated release”
Quote in the paperSubstantial claim- Also stated in: § Varenicline Acts as a Potent Partial Agonist at ␣62* nAChRs to Stimulate [ 3 H]Dopamine Release from Rat Striatal Synaptosomes. · plain
May combine two claims.
Findingown dataIn rats, varenicline has higher affinity than nicotine at both α6β2* and α4β2* nAChRs.
“Varenicline also had a higher affinity than nicotine at both the ␣62* and ␣42* nAChRs.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataVarenicline potently interacts at both α6β2* and α4β2* nAChRs in rat striatum.
“Varenicline potently interacts at both ␣62* and ␣42* nAChRs in rat striatum.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn rat striatum, varenicline is a partial agonist at both α6β2* and α4β2* nAChR subtypes.
“Work with ␣-CtxMII to delineate the contribution of the ␣62* and ␣42* nAChRs to varenicline-evoked release showed that varenicline was a partial agonist at both subtypes, in agreement with others (Grady et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Grady et al., 2010 source
Not checked in the free run.
May combine two claims.
Findingown dataIn acute experiments, varenicline has higher potency but is less efficacious than nicotine at α6β2* nAChRs in both monkey and rat striatum.
“The current results show that in acute experiments varenicline has a higher potency but is less efficacious than nicotine at ␣62* nAChRs in both monkey and rat striatum.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn monkey striatum, varenicline acts more potently than nicotine at both α6β2* and α4β2* nAChR subtypes.
“although varenicline seemed to act more potently at both subtypes than nicotine.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataVarenicline acts as a partial agonist at α6β2* and α4β2* nAChRs in both rat and monkey striatum.
“Varenicline acts as a partial agonist at ␣62* and ␣42* nAChRs in both rat and monkey striatum.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationVarenicline acts as a potent partial agonist at α4β2* nAChRs.
“numerous studies have shown that varenicline, a Food and Drug Administration-approved drug widely used to help people quit smoking, potently acts as a partial agonist at ␣42* nAChRs”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationMice lacking α4, α6, and/or β2 nAChR subunits do not self-administer nicotine, and restoring these subunits in the ventral tegmental area of knockout mice restores nicotine self-administration.
“Evidence for this idea stemmed from studies showing that mice lacking the ␣4, ␣6, and/or 2 nAChR subunits fail to self-administer nicotine, whereas re-expression of these subunits in the ventral tegmental area of knockout mice restored nicotine self-administration”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe mesolimbic dopamine system is a major contributor to reward function and addiction.
“Another critical site of action would be the mesolimbic dopamine system, which is a major contributor to reward function and addiction”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Dani and Bertrand, 2007
Not checked in the free run.
- cites De Biasi and Dani, 2011 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe striatum is implicated in the rewarding and addictive effects of nicotine.
“a region implicated in the rewarding and addictive effects of nicotine (Wise, 2009;Changeux, 2010).”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationThe effect of varenicline on α6β2* nAChR-mediated function in CNS dopaminergic systems is currently unclear.
“Although ␣62* nAChRs play an important role in addiction, the effect of varenicline on ␣62* nAChR-mediated function in CNS dopaminergic systems is currently unclear”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationVarenicline has significant effects at α7 nAChRs, α3β4* nAChRs, and 5-hydroxytryptamine type 3 receptors.
“subsequent work showed that varenicline had a significant effect at ␣7 nAChRs, ␣34* nAChRs, and 5-hydroxytryptamine type 3 receptors”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitationβ2, α4, or α6 nAChR knockout mice fail to self-administer nicotine.
“extensive studies showing that 2, ␣4, or ␣6 nAChRs knockout mice fail to self-administer nicotine (Picciotto et al., 1998;Marubio et al., 2003;Maskos et al., 2005;Pons et al., 2008).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe habenulo-interpeduncular pathway has been implicated in the addictive effects of smoking.
“as well as the habenulo-interpeduncular pathway, which has been implicated in the addictive effects of smoking (Dani and Bertrand, 2007;De Biasi and Dani, 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Dani and Bertrand, 2007
Not checked in the free run.
- cites De Biasi and Dani, 2011 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationNicotine exerts its rewarding effects by acting at nAChRs and increasing neurotransmission in the mesolimbic and nigrostriatal dopaminergic pathways.
“Nicotine seems to exert its rewarding effects by acting at nicotinic acetylcholine receptors (nAChRs) and increasing neurotransmission in the mesolimbic and nigrostriatal dopa-minergic pathways”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataOptical density measurements for the samples fell inside the standards' linear range.
“The sample optical density readings were within the linear range of the standards.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningDrugs targeting α6β2* nAChRs may be more selective for smoking cessation, with fewer side effects compared with varenicline, which activates multiple subtypes.
“drugs targeting ␣62* nAChRs may be more selective for smoking cessation, with fewer side effects compared with varenicline, which activates multiple subtypes.”
Quote in the paperSubstantial claim- Rests on an assumption: α6β2* nAChRs have a more restricted localization in the CNS than α4β2* nAChRs.
May combine two claims.
InterpretationreasoningDesensitization would result in a further reduction in dopamine release, with varenicline acting like a virtual antagonist.
“Desensitization would result in a further reduction in dopamine release, with varenicline acting like a virtual antagonist.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Monkeys serve as a valuable model for human comparison.
“We also evaluated varenicline's action in striatum of monkeys, a useful animal model for comparison with humans.”
The paper relies on this without support.
Nonhuman primate striatum more closely resembles human striatum than rat striatum in genetics, anatomy, and physiology.
“which offers the advantage that it more closely resembles humans with respect to genetics, anatomy, and physiology.”
The paper relies on this without support.
α6β2* nAChRs have a more restricted localization in the CNS than α4β2* nAChRs.
“Because ␣62* nAChRs exhibit a more restricted localization in the CNS than ␣42* nAChRs”
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?
Varenicline, an FDA-approved smoking cessation drug, acts as a partial agonist at α6β2* nAChRs.
“a non-nicotine pharmaceutical currently FDA approved for the treatment of smoking cessation, varenicline, acts as a partial agonist at α6β2* nAChRs (Grady et al. 2010; Bordia et al. 2012).”
From Nicotine Withdrawal (2015) · cites this paper as Bordia et al. 2012
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.
Monkey varenicline Ki values are described in the wrong direction
MinorThe discussion says varenicline's Ki values are several times greater than nicotine's, but the reported monkey values are smaller for both receptor subtypes. The paper elsewhere describes nicotine as having lower affinity than varenicline.
“Moreover, varenicline's K i values at both subtypes is several times greater than that observed for nicotine, as in the rat.”
“As for the rat, nicotine had a lower affinity than varenicline at both ␣62* and ␣42* nAChRs in monkey striatum.”
Cites
Guide for the Care and Use of Laboratory Animals: Eighth Edition
(2011) · doi:10.17226/12910 · Cited by 16,199 · see citing works
Jorenby, D. E. (2006) · JAMA · doi:10.1001/jama.296.1.56 · Cited by 1,635 · see citing works
Benowitz, N. L. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0809890 · Cited by 1,508 · see citing works
Picciotto, M. R., Zoli, M., Rimondini, R., Léna, C., Marubio, L. M., Pich, E. M., Fuxe, K., & Changeux, J.-P. (1998) · Nature · doi:10.1038/34413 · Cited by 1,320 · see citing works
Nicotinic Acetylcholine Receptors and Nicotinic Cholinergic Mechanisms of the Central Nervous System
Dani, J. A., & Bertrand, D. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105214 · Cited by 1,197 · see citing works
Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation
Coe, J. W., Brooks, P. R., Vetelino, M. G., Wirtz, M. C., Arnold, E. P., Huang, J., Sands, S. B., Davis, T. I., Lebel, L. A., Fox, C. B., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050069n · Cited by 930 · see citing works
The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine
Corrigall, W. A., Franklin, K. B. J., Coen, K. M., & Clarke, P. B. S. (1992) · Psychopharmacology · doi:10.1007/bf02245149 · Cited by 829 · see citing works
Corrigall, W. A., Coen, K. M., & Adamson, K. L. (1994) · Brain Research · doi:10.1016/0006-8993(94)90401-4 · Cited by 740 · see citing works
Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors
Maskos, U., Molles, B. E., Pons, S., Besson, M., Guiard, B. P., Guilloux, J.-P., Evrard, A., Cazala, P., Cormier, A., Mameli-Engvall, M., et al. (2005) · Nature · doi:10.1038/nature03694 · Cited by 566 · cited 4× · see citing works
“Such a mechanism of action to explain the effects of varenicline on smoking cessation is consistent with the result of extensive studies showing that 2, 4, or 6 nAChRs knockout mice fail to self-administer nicotine (Picciotto et al., 1998; Marubio et al., 2003; Maskos et al., 2005; Pons et al., 2008).”
BackgroundResultInfluentialVarenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors
Mihalak, K. B., Carroll, F. I., & Luetje, C. W. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.025130 · Cited by 558 · see citing works
Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction
Wise, R. A. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.06.004 · Cited by 500 · see citing works
Nicotine addiction and nicotinic receptors: lessons from genetically modified mice
Changeux, J.-P. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2849 · Cited by 453 · cited 3× · see citing works
“…nAChRs in CNS dopaminergic systems that mediate the addictive effects of nicotine are the 4 2* and 6 2* subtypes (the asterisk indicates the possible presence of other subunits in the receptor complex) (Barik and Wonnacott, 2009; Changeux, 2010; Mao and McGehee, 2010; De Biasi and Dani, 2011).”
BackgroundPICCIOTTO, M., ADDY, N., MINEUR, Y., & BRUNZELL, D. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.12.005 · Cited by 451 · cited 1× · see citing works
“This idea is consistent with an extensive literature suggesting that nicotine and other nAChR agonists induce their behavioral effects via this mechanism (Picciotto et al., 2008; Buccafusco et al., 2009; Bordia et al., 2010; Mineur and Picciotto, 2010; Grady et al., 2012).”
ResultRollema, H., Coe, J. W., Chambers, L. K., Hurst, R. S., Stahl, S. M., & Williams, K. E. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.05.003 · Cited by 400 · see citing works
Reward, addiction, withdrawal to nicotine
De Biasi, M., & Dani, J. A. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113734 · Cited by 366 · cited 6× · see citing works
“This action at 4 2* nAChRs is postulated to block the reinforcing effects of nicotine while also relieving craving and withdrawal symptoms (Biala et al., 2010; O’Connor et al., 2010; De Biasi and Dani, 2011; George et al., 2011).”
BackgroundInfluentialPons, S., Fattore, L., Cossu, G., Tolu, S., Porcu, E., McIntosh, J. M., Changeux, J. P., Maskos, U., & Fratta, W. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3918-08.2008 · Cited by 312 · see citing works
Self-citationNicotine receptors and depression: revisiting and revising the cholinergic hypothesis
Mineur, Y. S., & Picciotto, M. R. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.09.004 · Cited by 277 · see citing works
Marubio, L. M., Gardier, A. M., Durier, S., David, D., Klink, R., Arroyo‐Jimenez, M. M., McIntosh, J. M., Rossi, F., Champtiaux, N., Zoli, M., et al. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02564.x · Cited by 242 · see citing works
Self-citationExley, R., Clements, M. A., Hartung, H., McIntosh, J. M., & Cragg, S. J. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301617 · Cited by 242 · see citing works
Self-citationHatsukami, D. K., Stead, L. F., & Gupta, P. C. (2008) · The Lancet · doi:10.1016/s0140-6736(08)60871-5 · Cited by 227 · see citing works
Gotti, C., Guiducci, S., Tedesco, V., Corbioli, S., Zanetti, L., Moretti, M., Zanardi, A., Rimondini, R., Mugnaini, M., Clementi, F., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5095-09.2010 · Cited by 226 · see citing works
Suicidal Behavior and Depression in Smoking Cessation Treatments
Moore, T. J., Furberg, C. D., Glenmullen, J., Maltsberger, J. T., & Singh, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027016 · Cited by 150 · see citing works
Desensitization of nicotinic acetylcholine receptors as a strategy for drug development
Buccafusco, J. J., Beach, J. W., & Terry, A. V. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.145292 · Cited by 144 · cited 1× · see citing works
“This idea is consistent with an extensive literature suggesting that nicotine and other nAChR agonists induce their behavioral effects via this mechanism (Picciotto et al., 2008; Buccafusco et al., 2009; Bordia et al., 2010; Mineur and Picciotto, 2010; Grady et al., 2012).”
ResultThe Role of α6-Containing Nicotinic Acetylcholine Receptors in Nicotine Reward and Withdrawal
Jackson, K. J., McIntosh, J. M., Brunzell, D. H., Sanjakdar, S. S., & Damaj, M. I. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.155457 · Cited by 135 · see citing works
Self-citationO’Connor, E. C., Parker, D., Rollema, H., & Mead, A. N. (2010) · Psychopharmacology · doi:10.1007/s00213-009-1739-5 · Cited by 118 · see citing works
Shim, J.-C., Jung, D.-U., Jung, S. S., Seo, Y.-S., Cho, D.-M., Lee, J.-H., Lee, S.-W., Kong, B.-G., Kang, J.-W., Oh, M., et al. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.238 · Cited by 112 · see citing works
Vulnerability of125I-α-Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey
Quik, M., Polonskaya, Y., Kulak, J. M., & McIntosh, J. M. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-15-05494.2001 · Cited by 109 · see citing works
Self-citationMolecular and Cellular Mechanisms of Action of Nicotine in the CNS
Barik, J., & Wonnacott, S. (2009) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-69248-5_7 · Cited by 108 · see citing works
Chatterjee, S., Steensland, P., Simms, J. A., Holgate, J. Y., Coe, J. W., Hurst, R. S., Shaffer, C. L., Lowe, J. A., III, Rollema, H., & Bartlett, S. E. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.191 · Cited by 103 · see citing works
Brain nicotinic acetylcholine receptor occupancy: effect of smoking a denicotinized cigarette
Brody, A. L., Mandelkern, M. A., Costello, M. R., Abrams, A. L., Scheibal, D., Farahi, J. B., London, E. D., Olmstead, R. E., Rose, J. E., & Mukhin, A. G. (2008) · The International Journal of Neuropsychopharmacology · doi:10.1017/s146114570800922x · Cited by 101 · see citing works
Grady, S. R., Drenan, R. M., Breining, S. R., Yohannes, D., Wageman, C. R., Fedorov, N. B., McKinney, S., Whiteaker, P., Bencherif, M., Lester, H. A., et al. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.01.013 · Cited by 98 · see citing works
Kuryatov, A., & Lindstrom, J. M. (2010) · Molecular Pharmacology · doi:10.1124/mol.110.066159 · Cited by 97 · see citing works
Varenicline effects on craving, cue reactivity, and smoking reward
Brandon, T. H., Drobes, D. J., Unrod, M., Heckman, B. W., Oliver, J. A., Roetzheim, R. C., Karver, S. B., & Small, B. J. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2327-z · Cited by 96 · see citing works
Brunzell, D. H., Boschen, K. E., Hendrick, E. S., Beardsley, P. M., & McIntosh, J. M. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.171 · Cited by 95 · see citing works
Self-citationQuik, M., Sum, J., Whiteaker, P., McCallum, S. E., Marks, M. J., Musachio, J. L., McIntosh, J. M., Collins, A. C., & Grady, S. R. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.5.1169 · Cited by 83 · see citing works
Self-citationNicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization
Bordia, T., Campos, C., McIntosh, J. M., & Quik, M. (2010) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.162396 · Cited by 82 · cited 1× · see citing works
“This idea is consistent with an extensive literature suggesting that nicotine and other nAChR agonists induce their behavioral effects via this mechanism (Picciotto et al., 2008; Buccafusco et al., 2009; Bordia et al., 2010; Mineur and Picciotto, 2010; Grady et al., 2012).”
ResultSelf-citationPerez, X. A., Bordia, T., McIntosh, J. M., Grady, S. R., & Quik, M. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.048843 · Cited by 77 · see citing works
Self-citationVarenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine3 Receptor
Lummis, S. C. R., Thompson, A. J., Bencherif, M., & Lester, H. A. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.185306 · Cited by 71 · see citing works
Nicotine Reduces l-DOPA-Induced Dyskinesias by Acting at β2* Nicotinic Receptors
Huang, L. Z., Grady, S. R., & Quik, M. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.182949 · Cited by 70 · see citing works
Self-citationChapkis, W. (2013) · doi:10.4324/9781315811512-6 · Cited by 63 · see citing works
Biała, G., Staniak, N., & Budzyńska, B. (2010) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-010-0498-5 · Cited by 61 · see citing works
The use of 3H standards in 125I autoradiography
Artymyshyn, R. P., Smith, A., & Wolfe, B. B. (1990) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(90)90139-7 · Cited by 59 · see citing works
Meyer, E. L., Yoshikami, D., & McIntosh, J. M. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05266.x · Cited by 58 · see citing works
Self-citationGrady, S. R., Wageman, C. R., Patzlaff, N. E., & Marks, M. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.12.026 · Cited by 56 · see citing works
Pharmacotherapy for Smoking Cessation
Raupach, T., & van Schayck, O. C. P. (2011) · CNS Drugs · doi:10.2165/11590620-000000000-00000 · Cited by 52 · see citing works
Varenicline blocks nicotine intake in rats with extended access to nicotine self-administration
George, O., Lloyd, A., Carroll, F. I., Damaj, M. I., & Koob, G. F. (2010) · Psychopharmacology · doi:10.1007/s00213-010-2024-3 · Cited by 52 · see citing works
McCallum, S. E., Parameswaran, N., Bordia, T., McIntosh, J. M., Grady, S. R., & Quik, M. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.012773 · Cited by 52 · see citing works
Self-citationNicotine and Behavioral Sensitization
Mao, D., & McGehee, D. S. (2009) · Journal of Molecular Neuroscience · doi:10.1007/s12031-009-9230-7 · Cited by 49 · see citing works
Anderson, D. J., Malysz, J., Grønlien, J. H., El Kouhen, R., Håkerud, M., Wetterstrand, C., Briggs, C. A., & Gopalakrishnan, M. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.06.024 · Cited by 44 · see citing works
Repérant, C., Pons, S., Dufour, E., Rollema, H., Gardier, A. M., & Maskos, U. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.10.007 · Cited by 41 · see citing works
Dutra, S. J., Stoeckel, L. E., Carlini, S. V., Pizzagalli, D. A., & Evins, A. E. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2373-6 · Cited by 40 · see citing works
Maloku, E., Kadriu, B., Zhubi, A., Dong, E., Pibiri, F., Satta, R., & Guidotti, A. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.21 · Cited by 37 · see citing works
Compensation in pre‐synaptic dopaminergic function following nigrostriatal damage in primates
McCallum, S. E., Parameswaran, N., Perez, X. A., Bao, S., McIntosh, J. M., Grady, S. R., & Quik, M. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03610.x · Cited by 37 · see citing works
Self-citationSmoking cessation-recent advances
McNeil, J. J., Piccenna, L., & Ioannides-Demos, L. L. (2010) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-010-6246-8 · Cited by 31 · see citing works
Wooters, T. E., Smith, A. M., Pivavarchyk, M., Siripurapu, K. B., McIntosh, J. M., Zhang, Z., Crooks, P. A., Bardo, M. T., & Dwoskin, L. P. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01220.x · Cited by 28 · see citing works
Self-citationLotfipour, S., Mandelkern, M. A., Alvarez-Estrada, M., & Brody, A. L. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.20 · Cited by 26 · see citing works
Ortiz, N. C., O'Neill, H. C., Marks, M. J., & Grady, S. R. (2012) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntr284 · Cited by 22 · see citing works
Varenicline for tobacco dependence: panacea or plight?
Williams, J. M., Steinberg, M. B., Steinberg, M. L., Gandhi, K. K., Ulpe, R., & Foulds, J. (2011) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2011.587121 · Cited by 19 · see citing works
Dwoskin, L. P., & Bardo, M. T. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.157 · Cited by 15 · see citing works
α3 and α7 nAChR-mediated Ca2+ transient generation in IMR-32 neuroblastoma cells
Ween, H., Thorin‐Hagene, K., Andersen, E., Grønlien, J. H., Lee, C., Gopalakrishnan, M., & Malysz, J. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2010.06.005 · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Perez XA, Ly J, McIntosh JM, MQ (2011) Chronic nicotine exposure depresses dopaminergic function in nonhuman primate nucleus accumbens, at the Nicotinic Acetylcholine Receptors: Wellcome Trust Scientific Conference; 2011 May 18–21; Cambridge, UK. Wellcome Trust, London, UK.
Cited by
Sorted by citations
McLaughlin, I., Dani, J. A., & De Biasi, M. (2015) · Current Topics in Behavioral Neurosciences · doi:10.1007/978-3-319-13482-6_4 · Cited by 173 · see citing works
“Indeed, a non-nicotine pharmaceutical currently FDA approved for the treatment of smoking cessation, varenicline, acts as a partial agonist at α6β2* nAChRs (Grady et al. 2010; Bordia et al. 2012).”
BackgroundHendrickson, L. M., Guildford, M. J., & Tapper, A. R. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00029 · Cited by 132 · see citing works
“However, while varenicline was designed to be selective for α4β2 nAChRs at low doses, at high concentrations, varenicline is also a partial agonist at α6β2 nAChRs, a full agonist at α3β4 and α7 nAChRs, as well as at 5-HT3 receptors (Mihalak et al., 2006; Papke et al., 2010; Lummis et al., 2011; Bordia et al., 2012), w…”
BackgroundNeurobiological Mechanisms of Nicotine Reward and Aversion
Wills, L. P., Ables, J. L., Braunscheidel, K. M., Caligiuri, S. P. B., Elayouby, K. S., Fillinger, C., Ishikawa, M., Moen, J. K., & Kenny, P. J. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000299 · Cited by 126 · see citing works
“a6b2* nAChRs are activated by cytisine and varenicline far more efficiently than other b2* nAChRs (Salminen et al., 2004; Bordia et al., 2012), suggesting that they may contribute to the clinical utility 278 Wills et al.”
BackgroundWirta, D., Vollmer, P. M., Paauw, J. D., Chiu, K.-H., Henry, E., Striffler, K., Nau, J. A., Wirta, D., Rubin, J. M., Reilly, C. D., et al. (2021) · Ophthalmology · doi:10.1016/j.ophtha.2021.11.004 · Cited by 105 · see citing works
Medications for alcohol use disorders: An overview
Akbar, M. D., Egli, M., Cho, Y., Song, B., & Noronha, A. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.11.007 · Cited by 97 · 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
The Biological Impact of Menthol on Tobacco Dependence
Wickham, R. J. (2019) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntz239 · Cited by 80 · see citing works
Nicotine and Nicotinic Receptor Drugs
Quik, M., Bordia, T., Zhang, D., & Perez, X. A. (2015) · International review of neurobiology · doi:10.1016/bs.irn.2015.07.005 · Cited by 66 · see citing works
Self-citationRole for the nicotinic cholinergic system in movement disorders; therapeutic implications
Quik, M., Zhang, D., Perez, X. A., & Bordia, T. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.05.004 · Cited by 62 · see citing works
Self-citationNicotine reduces established levodopa‐induced dyskinesias in a monkey model of Parkinson's disease
Quik, M., Mallela, A., Ly, J., & Zhang, D. (2013) · Movement Disorders · doi:10.1002/mds.25594 · Cited by 60 · see citing works
Self-citationAddiction‐related neuroadaptations following chronic nicotine exposure
Wills, L., & Kenny, P. J. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15356 · Cited by 61 · see citing works
Powers, M. S., Broderick, H. J., Drenan, R. M., & Chester, J. A. (2013) · Genes Brain & Behavior · doi:10.1111/gbb.12042 · Cited by 49 · see citing works
“Varenicline, an FDA-approved smoking cessation drug and partial agonist at α4β2* and α6β2* nAChRs (Bordia et al. 2012; Mihalak et al. 2006) acts via VTA nAChRs to attenuate alcohol consumption (Hendrickson et al. 2010; Zhao-Shea et al. 2011).”
BackgroundZhang, D., Mallela, A., Sohn, D., Carroll, F. I., Bencherif, M., Letchworth, S. R., & Quik, M. (2013) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.207639 · Cited by 49 · see citing works
“Although initial studies suggested that varenicline was selective for a4b2* nAChRs, subsequent work showed that it also interacted with a6b2*, a3b4*, and a7 nAChRs (Coe et al., 2005; Mihalak et al., 2006; Grady et al., 2010; Ween et al., 2010; Chatterjee et al., 2011; Bordia et al., 2012).”
BackgroundSelf-citationVarenicline Solution Nasal Spray: A Review in Dry Eye Disease
Frampton, J. E. (2022) · Drugs · doi:10.1007/s40265-022-01782-4 · Cited by 47 · see citing works
Quik, M., Campos, C., & Grady, S. R. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.06.027 · Cited by 49 · see citing works
“There are currently no a4b2* nor a6b2* selective nAChR compounds available to evaluate the separate role of these subtypes in behavior [30,52,53].”
Self-citationABT‐089 and ABT‐894 reduce levodopa‐induced dyskinesias in a monkey model of Parkinson's disease
Zhang, D., Bordia, T., McGregor, M. M., McIntosh, J. M., Decker, M. W., & Quik, M. (2014) · Movement Disorders · doi:10.1002/mds.25817 · Cited by 45 · see citing works
“To evaluate binding, optical density readings were converted to fmol/mg tissue using (125)I-standards, as previously described.(19,37)”
MethodSelf-citationLiu, L., Zhao-Shea, R., McIntosh, J. M., & Tapper, A. R. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.06.015 · Cited by 40 · see citing works
Self-citationGrasing, K. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.06.022 · Cited by 38 · see citing works
Recent Advances in the Pharmacology of Tardive Dyskinesia
Caroff, S. N. (2020) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2020.18.4.493 · Cited by 31 · see citing works
“should acutely worsen TD, but long-term administration leading to nAChR desensitization may reduce dopamine release and potentially suppress dyskinesias [111,114].”
BackgroundBupropion–varenicline interactions and nicotine self-administration behavior in rats
Hall, B. J., Slade, S. K., Wells, C., Rose, J. E., & Levin, E. D. (2015) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2015.01.009 · Cited by 31 · see citing works
“Varenicline is a partial agonist at α4β2*, α6β2* and α3β4 nAChRs, and a full agonist at α7 nAChRs (Bordia et al., 2012;Mihalak et al., 2006; Rollema et al., 2007); in 2006, varenicline became the first non-nicotine therapeutic to be approved by the FDA specifically to treat tobacco addiction.”
Berry, J. N., Engle, S. E., McIntosh, J. M., & Drenan, R. M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.07.052 · Cited by 30 · see citing works
Self-citationLiu, W., & Li, M. D. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170801103009 · Cited by 27 · see citing works
“In practice, varenicline is a non-nicotine pharmaceutical that can act as a partial agonist at α6β2* nAChRs, and it is currently approved for the treatment of NA and SC [208, 209].”
BackgroundPerez, X. A., Khroyan, T. V., McIntosh, J. M., & Quik, M. (2014) · Pharmacology Research & Perspectives · doi:10.1002/prp2.105 · Cited by 29 · see citing works
“Both nicotine and varenicline interact equally well with a4b2* and a6b2* nAChRs, with varenicline acting as a partial agonist with higher potency than nicotine at these nAChR subtypes (Grady et al. 2010; Bordia et al. 2012).”
BackgroundSelf-citationMello, N. K., Fivel, P. A., Kohut, S. J., & Carroll, F. I. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.325 · Cited by 26 · see citing works
Pflugfelder, S. C., Cao, A. C., Galor, A., Nichols, K. K., Cohen, N. A., & Dalton, M. (2022) · The Ocular Surface · doi:10.1016/j.jtos.2022.05.001 · Cited by 24 · see citing works
Bordia, T., McIntosh, J. M., & Quik, M. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12179 · Cited by 23 · see citing works
“The sections were thaw mounted onto poly-L-lysinecoated slides, dried, and stored at 80°C. Nicotine-evoked 3H-dopamine release Nicotine-evoked 3H-dopamine release from the rat striatal synaptosomes was performed as described (Quik et al. 2003; Bordia et al. 2012).”
BackgroundMethodSelf-citationOon‐arom, A., Likhitsathain, S., & Srisurapanont, M. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.107631 · Cited by 21 · see citing works
Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice
Kamens, H. M., Silva, C. P., Peck, C., & Miller, C. N. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.07.020 · Cited by 19 · see citing works
“, 2007), it is also known to interact with other nicotinic receptors (α3β4, α6β2, and α7) at high concentrations (Bordia et al., 2012; Mihalak et al., 2006) and it is possible that multiple nAChRs may mediate some of its actions.”
BackgroundBarrett, S. T., Geary, T. N., Steiner, A. N., & Bevins, R. A. (2018) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000404 · Cited by 16 · see citing works
“Varenicline acts as a full agonist at α7 receptors with high binding affinity, and activates α6β2* and α3β4* receptors (Mihalak et al., 2006; Rollema et al., 2007; Grady et al., 2010; Bordia et al., 2012; Ortiz et al., 2012).”
Design, Synthesis and Discovery of Picomolar Selective α4β2 Nicotinic Acetylcholine Receptor Ligands
Yenugonda, V. M., Xiao, Y., Levin, E. D., Rezvani, A. H., Tran, T. P., Al‐Muhtasib, N., Sahibzada, N., Xie, T., Wells, C., Slade, S. K., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4008455 · Cited by 17 · see citing works
Patkar, O. L., Belmer, A., Tarren, J. R., Holgate, J. Y., & Bartlett, S. E. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.09.048 · Cited by 17 · see citing works
Hone, A. J., McIntosh, J. M., Rueda‐Ruzafa, L., Passas, J., Guerín, C. D. C., Blázquez, J., Enguita, C. G., & Albillos, A. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13883 · Cited by 15 · see citing works
“However, varenicline has also been shown to activate other human nAChR subtypes implicated in nicotine addiction including a6b2b3, a3b4, and a7 (Capelli et al. 2011; Bordia et al. 2012; Stokes and Papke 2012; Campling et al. 2013).”
BackgroundSelf-citationGao, R., Schneider, A. M., Mulloy, S., & Lee, A. M. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.16109 · Cited by 11 · see citing works
“Varenicline is approved for nicotine dependence and was designed as a partial agonist targeting the α 4 β 2 subtype (Rollema et al., 2007) but has additional partial agonist activity at the α 6* subtype and full agonist activity at the α 7 subtype (Bordia et al., 2012; Mihalak et al., 2006).”
Pharmacological Options for Smoking Cessation in Heavy-Drinking Smokers
Yardley, M. M., Mirbaba, M., & Ray, L. A. (2015) · CNS Drugs · doi:10.1007/s40263-015-0284-5 · Cited by 14 · see citing works
“Varenicline is a partial agonist at multiple heteromeric nAChRs, including a4b2 [58], a3b4 [59], and a6b2 nAChRs [60], as well as a full agonist at a7 nAChRs [61].”
Ondachi, P. W., Castro, A. H., Bartkowiak, J., Luetje, C. W., Damaj, M. I., Mascarella, S. W., Navarro, H. A., & Carroll, F. I. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401602p · Cited by 14 · see citing works
Cohen, G. A., Bellanca, C. M., Bernardini, R., Rose, J. E., & Polosa, R. (2024) · iScience · doi:10.1016/j.isci.2024.111090 · Cited by 15 · see citing works
Neuronal nicotinic acetylcholine receptors mediate ∆ 9 ‐THC dependence: Mouse and human studies
Donvito, G., Muldoon, P. P., Jackson, K. J., Ahmad, U., Zaveri, N. T., McIntosh, J. M., Chen, X., Lichtman, A. H., & Damaj, M. I. (2018) · Addiction Biology · doi:10.1111/adb.12691 · Cited by 13 · see citing works
Self-citationCollo, G., Cavalleri, L., Zoli, M., Maskos, U., Ratti, E., & Pich, E. M. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00572 · Cited by 10 · see citing works
Improvement of Restless Legs Syndrome by Varenicline as Antismoking Treatment
Romigi, A., & Vitrani, G. (2013) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.3092 · Cited by 10 · see citing works
Carroll, F. I., Navarro, H. A., Mascarella, S. W., Castro, A. H., Luetje, C. W., Wageman, C. R., Marks, M. J., Jackson, A. B., & Damaj, M. I. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00077 · Cited by 10 · see citing works
“nAChRs, respectively.(19) In monkeys varenicline potently inhibited striatal α6β2*- and α4β2*nAChR with Ki values of 0.”
Nilges, M. R., Laurent, M., Cable, C., Arens, L., Vafiades, J., & Zadina, J. E. (2019) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.253013 · Cited by 10 · see citing works
“Although DD is typically used to indicate that the test drug may be abused if subsequent CPP or SA tests confirm abuse liability (Swedberg, 2016), it may also indicate that the test drug is similar to the training drug but dissociable from the reward properties of the training drug (Ator, 2002), as is the case with th…”
ResultZhou, X., Huang, Z., Song, Q., Xia, X., Cheng, A., Liu, Z., Wang, M., Ji, T., Aihemaiti, A., Xie, Y., et al. (2025) · Addiction · doi:10.1111/add.70235 · Cited by 9 · see citing works
The role of nicotinic receptors in alcohol consumption
Kamens, H. M., Flarend, G., & Horton, W. J. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106705 · Cited by 8 · see citing works
Hauswirth, S. G., Kabat, A. G., Hemphill, M., Somaiya, K., Hendrix, L. H., & Gibson, A. (2023) · Journal of Comparative Effectiveness Research · doi:10.57264/cer-2022-0215 · Cited by 9 · see citing works
Varenicline Prevents SARS-CoV-2 Infection In Vitro and in Rhesus MacaquesPreprint
Nau, J. A., Luthra, P., Lanzer, K. G., Szaba, F. M., Cookenham, T. S., & Carlson, E. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.29.450426 · Cited by 8 · see citing works
Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine‐A
Touchette, J. C., Moen, J. K., Robinson, J. M., & Lee, A. M. (2020) · Addiction Biology · doi:10.1111/adb.12908 · Cited by 6 · see citing works
Varenicline solution nasal spray for dry eye disease in Chinese patients: a randomized phase 3 trial
Tian, L., Jin, X., Wang, J., Xu, Y.-G., Lü, C.-W., Zhao, S., Zhu, Q., Dai, H., Gu, H., Zhang, M., et al. (2024) · The Lancet Regional Health - Western Pacific · doi:10.1016/j.lanwpc.2024.101032 · Cited by 6 · see citing works
Unraveling the Role of CHRNA6, the Neuronal α6 Nicotinic Acetylcholine Receptor Subunit
Heydary, Y. H., Castro, E. M., Lotfipour, S., & Leslie, F. M. (2025) · Receptors · doi:10.3390/receptors4010001 · Cited by 6 · see citing works
Effects of adolescent substance use disorders on central cholinergic function
Hauser, S. R., Rodd, Z. A., Deehan, G. A., Liang, T., Rahman, S., & Bell, R. L. (2021) · International review of neurobiology · doi:10.1016/bs.irn.2021.07.008 · Cited by 7 · see citing works
Administration of Nicotine Can Inhibit Myopic Growth in Animal Models
Thomson, K., Karouta, C., & Ashby, R. (2024) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.65.11.29 · Cited by 5 · see citing works
Varenicline for the Treatment of Cocaine Dependence
Lynch, K. G., Plebani, J. G., Spratt, K. A., Morales, M., Tamminga, M. A., Feibush, P., & Kampman, K. M. (2021) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000842 · Cited by 5 · see citing works
“Varenicline is also a full agonist at the a7 receptors(11,12) and a partial agonist at the a6b2 receptors.(13,14) Both a7 and a6b2 receptors are implicated in the neural reward circuitry activated by cocaine use(12,15,16) and full agonism at the a7 receptor may reduce cocaine withdrawal and craving.”
BackgroundOndachi, P. W., Castro, A. H., Luetje, C. W., Wageman, C. R., Marks, M. J., Damaj, M. I., Mascarella, S. W., Navarro, H. A., & Carroll, F. I. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00107 · Cited by 5 · see citing works
Breining, S. R., Genus, J. F., Mitchener, J. P., Cuthbertson, T. J., Heemstra, R. J., Melvin, M. S., Dull, G. M., & Yohannes, D. (2013) · Organic Process Research & Development · doi:10.1021/op400002r · Cited by 4 · see citing works
Trigo, J. M., & Foll, B. L. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9554-7_11 · Cited by 3 · see citing works
Effect of Varenicline on Tardive Dyskinesia: A Pilot Study
Caroff, S. N., Gutman, A. R., Northrop, J., Leong, S. H., Berkowitz, R. M., & Campbell, E. C. (2021) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2021.19.2.355 · Cited by 2 · see citing works
“Based on animal studies [15,16], we anticipated that varenicline would reduce severity of TD.”
BackgroundGao, R., Schneider, A. M., Mulloy, S. M., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.28.537363 · Cited by 2 · see citing works
A review of dry eye disease therapies: exploring the qualities of varenicline solution nasal spray
Bhargava, S., Panda, R., Azam, A. M., & Sheppard, J. D. (2023) · Expert Review of Ophthalmology · doi:10.1080/17469899.2023.2173173 · Cited by 1 · see citing works
He, C.-Z., Qiu, Q., Lu, S.-J., Xue, F.-L., Wang, W., & He, Y. (2025) · Medicine · doi:10.1097/md.0000000000045032 · Cited by 1 · see citing works
“[6,7] Tyrvaya is speculated to influence the trigeminal nerve endings in the anterior nasal cavity, thereby activating the nasolacrimal reflex.”
Neuronal Nicotinic Acetylcholine Receptors in Reward and Addiction
Hendrickson, L. M., & Tapper, A. R. (2014) · The Receptors · doi:10.1007/978-1-4939-1167-7_15 · Cited by 2 · see citing works
Danpanichkul, P., Pang, Y., Kim, D., Suenghataiphorn, T., Ko, D., Ibrahim, A., Prasitsumrit, V., Duangsonk, K., Noureddin, M., Wijarnpreecha, K., et al. (2025) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.70160 · Cited by 1 · see citing works
Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-APreprint
Touchette, J. C., Moen, J. K., Robinson, J. M., & Lee, A. M. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/723916 · Cited by 1 · see citing works
Soll, L. G. (2013) · eScholarship@UMassChan · doi:10.13028/m2ng64
“…varenicline, a partial agonist of α4β2* and α6β2* nAChRs (and a current smoking cessation drug), alleviates CFC during nicotine withdrawal, thus further confirming their role and indicating β2* nAChRs as good therapeutic targets for nicotine cessation (Raybuck et al., 2008, Bordia et al., 2012).”
BackgroundBarrett, S. T. (2014) · Lincoln (University of Nebraska)
Drugs to Treat Substance Use Disorders
Sinclair, J., & Peters, L. (2020) · Cambridge University Press eBooks · doi:10.1017/9781911623465.017
Agents for Treatment of Withdrawal and Dependency: Varenicline
Jacob, C. C., & Polak, T. T. (2020) · Springer eBooks · doi:10.1007/978-3-319-56015-1_350-1
Agents for Treatment of Withdrawal and Dependency: Varenicline
Jacob, C. C., & Polak, T. T. (2022) · Springer eBooks · doi:10.1007/978-3-030-62059-2_350
Bernat, P., Kołodziejczyk, P., Łuszczki, J. J., Zagaja, M. P., & Tutka, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032616
“Molecular mechanisms of action of VAR are linked to a full agonism on α7 nAChRs and a partial agonism on the α4β2, α3β4, and α6β2 subtypes of nAChRs [37,38].”
BackgroundChaudhari, P., Shaji, A. K., Lewis, S. A., Prasad, S., Priyanka, & Kour, A. (2026) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2026.108331
McLean, N. A., Greenway, A. E., Gray, T. L., Stiles, S. N. S., Denton, T. T., & Rossi, D. J. (2026) · Neuropharmacology · doi:10.1016/j.neuropharm.2026.111029
Almutawtah, S., AlFoudari, Y., Mohammad, A., et al. (2026) · International Ophthalmology · doi:10.1007/s10792-026-04178-5
“The strong effect of nasal varenicline on STS is consistent with the proposed mechanism of varenicline as a nAChR agonist that activates the trigeminal parasympathetic pathway represented in nasolacrimal reflex to stimulate basal tear production [13, 32].”
- Authors
- Bordia, T., Hrachova, M., Chin, M., McIntosh, J. M., & Quik, M.
- Affiliations
- SRI International (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 342
- Issue
- 2
- Pages
- 327-334
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC3400806
- OpenAlex
- W2070026700
- Semantic Scholar
- 3dcd1c1078bfabd5260d3c9d7efb65975a9a93d6
- Cited by
- 70
- References
- 61
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 6 · 2014: 6 · 2013: 12
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tobacco-Related Disease Research Program (17RT-0119)
- National Institutes of Health
- National Institute on Drug Abuse (DA 015663, P30DA015663)
- National Institute of Neurological Disorders and Stroke (NS59910, R21NS065851, NS65851, R01NS059910)
- 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
- varenicline, α4β2 nicotinic acetylcholine receptor, partial agonism, striatum, dopamine release, nicotine, receptor binding affinity, nicotine craving, nicotine withdrawal, nicotine reinforcement, synaptosomes, monkey model, rat model, receptor selectivity, smoking cessation drugs
- MeSH terms
- Varenicline, Animals, Benzazepines, Corpus Striatum, Dopamine, Male, Nicotine, Protein Binding, Quinoxalines, Receptors, Nicotinic, Saimiri, Synaptosomes, Smoking Cessation, Rats, Sprague-Dawley, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.
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
