CoChat
Sign Up
Cited by 145Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchSmoking Behavior and Cessation

Desensitization of nicotinic acetylcholine receptors as a strategy for drug development

Open access
Buccafusco, Jerry J., Beach, J. Warren, Terry, Alvin V.·2009·The Journal of Pharmacology and Experimental Therapeutics
DOI 10.1124/jpet.108.145292PMC PMC2682277
Open this paper in CoChat — free accountOpen PDF

Abstract

The specific pharmacological response evoked by a nicotinic acetylcholine receptor (nAChR) agonist is governed by the anatomical distribution and expression of each receptor subtype and by the stoichiometry of subunits comprising each subtype. Contributing to this complexity is the ability of agonists that bind to the orthosteric site of the receptor to alter the affinity state of the receptor and induce desensitization and the observation that, at low doses, some nAChR antagonists evoke agonist-like nicotinic responses. Brain concentrations of nicotine rarely increase to the low-mid micromolar concentrations that have been reported to evoke direct agonist-like responses, such as calcium influx or neurotransmitter release. Low microgram per kilogram doses of nicotine administered to humans or to nonhuman primates to improve cognition and working memory probably result only in low nanomolar brain concentrations--more in line with the ability of nicotine to induce receptor desensitization. Here we review data illustrating that nicotine, its major metabolite cotinine, and two novel analogs of choline, JWB1-84-1 [2-(4-(pyridin-3-ylmethyl)piperazin-1-yl)ethanol] and JAY2-22-33, JWB1-84-1 [2-(methyl(pyridine-3-ylmethyl)amino)-ethanol], improve working memory in macaques. The effectiveness of these four compounds in the task was linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation evoked by a nAChR agonist in rats. Only nicotine evoked an agonist-like action (increased resting blood pressure). Therefore, it is possible to develop new chemical entities that have the ability to desensitize nAChRs without an antecedent agonist action. Because these "silent desensitizers" are probably acting allosterically, an additional degree of subtype specificity could be attained.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the cognitive and behavioral effects of nicotine and related compounds may be mediated more by nicotinic acetylcholine receptor (nAChR) desensitization than by direct receptor activation. It presents data in rats and macaques suggesting that “silent desensitizers” can improve working memory without an antecedent agonist-like action.

Key findings

  • Brain concentrations of nicotine after low microgram per kilogram doses in humans or nonhuman primates are probably only low nanomolar, more consistent with nAChR desensitization than with the low-mid micromolar concentrations needed for direct agonist-like calcium influx or neurotransmitter release.
  • In a rat ganglionic nAChR assay using DMPP-induced pressor responses, nicotine, cotinine, JWB1-84-1, and JAY2-22-33 produced desensitization; only nicotine increased resting blood pressure, indicating an agonist-like action. Cotinine appeared most efficacious, while JWB1-84-1 was nearly as effective across a wider dose range.
  • All four compounds improved delayed matching-to-sample (DMTS) working memory accuracy in macaques, predominantly at long delay intervals; the increase in accuracy was linearly related to the ability to desensitize ganglionic nAChRs, although the authors note this is based on only four data points.
  • Sazetidine-A is described as a possible “silent desensitizer” at α4β2 nAChRs: after as little as 10 min pretreatment it inhibited subsequent nicotine-evoked 86Rb+ release and was 50-fold more potent than dihydro-β-erythroidin in this regard.

Methods

  • Narrative review/perspective synthesizing prior literature and presenting original data from rat and macaque experiments.
  • Rat experiments: freely moving adult rats with aortic and jugular catheters received a 20-min intravenous infusion of test compound or vehicle, followed by a 5-min rest and a bolus of DMPP; mean arterial pressure was recorded, and desensitization was measured as the DMPP-induced MAP area over the first 10 min, expressed as percentage of vehicle control.
  • Macaque DMTS experiments: 96-trial sessions with zero, short, medium, and long delay intervals; data from n = 8–13 subjects were averaged at best doses and plotted against maximal decreases in MAP, with a linear regression through the mean values.

Limitations

  • The authors state that the correlation between desensitization and memory improvement rests on only four data points, so it is suggestive rather than definitive.
  • The authors state that the situation is more complicated, that further studies are needed, that it remains to be determined which sazetidine-A actions are attributable to silent desensitization, and that greater knowledge of human nAChR subtype expression and stoichiometry is required.
  • Evident from the text: this is a review with original data drawn from multiple prior and unpublished studies, the cross-compound correlation is not causal, and some experimental details are referred to elsewhere rather than fully reported here.

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

Integrity signals

Registry

Crossref · 10.1124/jpet.108.145292

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 41 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The four compounds' effectiveness in the working memory task is linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation by a nicotinic agonist in rats.

    “The effectiveness of these four compounds in the task was linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation evoked by a nAChR agonist in rats.”
    Quote in the paperSubstantial claim
  • Findingown data

    JWB1-84-1 improves spatial working memory accuracy in transgenic mice carrying Alzheimer's disease-related amyloid precursor protein-Swedish and PS1 mutations.

    “JWB1-84-1 improved accuracy in a spatial working memory task by transgenic mice bearing the amyloid precursor protein-Swedish mutation/PS1 mutations related to Alzheimer's disease.”
    Quote in the paperSubstantial claim
  • Findingown data

    JWB1-84-1 and JAY2-22-33 were ineffective at displacing other labeled nAChR ligands, such as [3H]epibatidine, from rat brain membrane binding sites.

    “In fact, the compounds were ineffective in displacing other labeled nAChR ligands such as [ 3 H]epibatidine from binding sites on rat brain membranes.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Even at doses up to 13 times that of nicotine, cotinine alone did not significantly affect blood pressure.

    “cotinine produced no significant effects on blood pressure of its own at up to 13 times the dose of nicotine (Buccafusco et el., 2007b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Buccafusco et el., 2007b

      Not checked in the free run.

  • Findingown data

    There was a very high degree of correlation between the increase in DMTS task accuracy and the ability to desensitize ganglionic nAChRs across the four compounds.

    “It is surprising that there was a very high degree of correlation between the two.”
    Quote in the paperSubstantial claim
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingreasoning

    Nicotine, cotinine, JWB1-84-1, and JAY2-22-33 improve working memory in macaques.

    “Here we review data illustrating that nicotine, its major metabolite cotinine, and two novel analogs of choline, JWB1-84-1 [2-(4-(pyridin-3-ylmethyl)piperazin-1-yl)ethanol] and JAY2-22-33, JWB1-84-1 [2-(methyl(pyridine-3-ylmethyl)amino)ethanol], improve working memory in macaques.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    JWB1-84-1 improves delayed matching-to-sample accuracy in aged monkeys and reverses distractor-impaired accuracy in young macaques in an attention deficit model.

    “The compound also improved DMTS task accuracy by aged monkeys and significantly reversed distractor-impaired accuracies in an attention deficit model in young macaques (Sood et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sood et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Neither JWB1-84-1 nor any other tested choline analog displaced alpha7 ligands in competition binding assays.

    “Therefore, it was quite surprising to determine that neither compound nor any of the other analogs that was tested exhibited any ability to displace ␣7 ligands in competition binding assays.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    JAY2-22-33 shows similar properties in this model but perhaps less effectively than JWB1-84-1.

    “JAY2-22-33 exhibited similar properties in this model but perhaps not as effectively as JWB1-84-1 (unpublished data).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites unpublished data

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    JWB1-84-1 and JAY2-22-33 did not displace α7 ligands in competition binding assays.

    “exhibited any ability to displace ␣7 ligands in competition binding assays.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In a screen of 40 potential drug targets, JWB1-84-1 and JAY2-22-33 showed no significant interactions, except for an unconfirmed interaction between JAY2-22-33 and the H3 histamine receptor.

    “There were no significant interactions in the screen of 40 potential drug targets, with the exception of JAY2-22-33 and H3 histamine receptor interaction; however, this interaction has not been confirmed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among these compounds, only nicotine produced an agonist-like action, increased resting blood pressure.

    “Only nicotine evoked an agonist-like action (increased resting blood pressure).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In macaques, all four compounds significantly enhanced DMTS task accuracy, especially at long delay intervals.

    “All four compounds significantly improved task accuracy, with predominant effects during long delay intervals (representing retention/retrieval components of working memory).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Buccafusco et al., 1999

      Not checked in the free run.

    • cites Terry et al., 2005

      Not checked in the free run.

    • cites Sood et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Nicotine and cotinine both readily desensitized nAChRs to the stimulus effects of DMPP.

    “In this paradigm, both nicotine and cotinine readily desensitized nAChRs to the stimulus properties of the ganglionic, nicotinic agonist dimethylphenylpiperazinium (DMPP).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the DMPP paradigm, cotinine seemed most efficacious at desensitizing ganglionic nAChRs, while JWB1-84-1 was nearly as effective but across a wider dose range.

    “Although cotinine seemed to be most efficacious in this regard, JWB1-84-1 evoked a response that was nearly as effective but was observable across a wider dose range.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Agonist binding at the orthosteric site can change a nicotinic receptor's affinity state and cause desensitization.

    “Contributing to this complexity is the ability of agonists that bind to the orthosteric site of the receptor to alter the affinity state of the receptor and induce desensitization”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Almost all new nicotinic agonists developed in the past two decades can desensitize nicotinic receptors, but most do so by first activating the orthosteric site.

    “In fact, almost all of the new agonists developed in the past two decades have the potential to desensitize nAChRs; however, most of these accomplish this action by first activating the receptor at the orthosteric site.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sazetidine-A exhibits high affinity and selectivity for the alpha4beta2 nicotinic receptor subtype in equilibrium binding assays.

    “Sazetidine-A exhibited high affinity and selectivity in equilibrium binding assays for the ␣4␤2 subtype of nAChRs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xiao et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cotinine is described as a weak nicotinic agonist that can cause partial desensitization of nAChRs.

    “Cotinine has been characterized as a weak nicotinic agonist capable of evoking partial nAChR desensitization (Briggs et al., 1999;Vainio and Tuominen, 2001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Briggs et al., 1999

      Not checked in the free run.

    • cites Vainio and Tuominen, 2001

      Not checked in the free run.

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

    Premisecitation

    Positive allosteric modulators facilitate endogenous neurotransmission without directly stimulating target receptors and have been known for nicotinic receptors for several years.

    “Positive allosteric modulators, defined as compounds that facilitate endogenous neurotransmission without directly stimulating the target receptors, have been known for ligandgated ion channel receptors, including nAChRs, for several years (see Albuquerque et al., 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Albuquerque et al., 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nicotine and mecamylamine both increase serotonin release in rat dorsal hippocampal slices.

    “Moreover, both nicotine and mecamylamine increased serotonin release in rat dorsal hippocampal slices (Kenny et al., 2000)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kenny et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microgram per kilogram doses of nicotine and mecamylamine enhance delayed matching-to-sample accuracy in monkeys and improve delayed stimulus discrimination performance in rats.

    “For example, microgram per kilogram doses of nicotine and mecamylamine each have been observed to enhance delayed matching-to-sample (DMTS) accuracy in monkeys (Buccafusco and Jackson, 1991;Terry et al., 1999) and to improve the performance by rats of a delayed stimulus discrimination task (Terry et al., 1999).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Buccafusco and Jackson, 1991

      Not checked in the free run.

    • cites Terry et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because brain nicotine and cotinine concentrations after smoking are insufficient to induce neurotransmitter release, both compounds could act behaviorally through nicotinic receptor desensitization.

    “Because brain nicotine and cotinine concentrations after smoking are not sufficient to induce neurotransmitter release, both compounds could mediate their behavioral actions through nAChR desensitization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PNU-120596 acts as a positive allosteric modulator of nicotinic receptors both in vitro and in vivo.

    “A more relevant proof of concept is derived from studies with the compound PNU-120596, which has been demonstrated to act as a positive allosteric modulator of nAChRs both in vitro and in vivo (Hurst et al., 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hurst et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The idea that nicotine's central nervous system effects arise solely from agonist action at nicotinic receptors and subsequent neurotransmitter release is probably too simple, because nicotine and nicotinic antagonists can have similar physiological effects in several settings.

    “The concept that the central nervous system effects of nicotine are due to its”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sazetidine-A produces no agonist-like effect, but pretreatment for as little as 10 minutes inhibits subsequent nicotine-evoked 86Rb+ release.

    “Despite its affinity for the orthosteric site of the receptor, the compound evoked no agonist-like effect; however, pretreatment for as little as 10 min with the drug inhibited the subsequent response ( 86 Rb ϩ release) evoked by nicotine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xiao et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Positive allosteric modulators such as PNU-120596 enable nicotinic neurotransmission largely by preventing desensitization and cannot desensitize nicotinic receptors on their own.

    “However, positive allosteric modulators such as PNU-120596 enable nicotinic cholinergic neurotransmission in large part by preventing desensitization, and on their own, they cannot desensitize nAChRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Nicotinic receptors exist in rapidly interconvertible conformational states; agonist binding stabilizes a high-affinity desensitized state and reduces responsiveness to a subsequent stimulus.

    “nAChRs can exist in various conformational states that are rapidly interconvertible.Agonist binding stabilizes the desensitized state, which is characterized by the high-affinity binding of agonists.Despite the conversion to a high-affinity state, desensitization results in decreased responsiveness of the receptor for a subsequent stimulus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The agonist approach has not produced highly subtype-selective ligands, and many compounds share side-effect profiles with nicotine.

    “The problem with this approach is that it has not generated very highly subtype-selective ligands, and many compounds share side-effect profiles with nicotine.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Targeting allosteric sites on nicotinic receptors could improve subtype selectivity.

    “Targeting allosteric sites on nAChRs could be one approach to potentially improve subtype selectivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    The model provides a basis for new drug discovery.

    “However, the model provides a basis for new drug discovery.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: There is a direct relationship between the three systems: acetylcholine activates nicotinic receptors on GABA interneurons in the hippocampus, which inhibits primary hippocampal glutamate neurons.
    • The authors state this as an assumption: When acetylcholine is overactivated or a nAChR agonist is administered, the first response is further activation of the GABA interneuron.
    • The authors state this as an assumption: Because α7 nAChRs rapidly desensitize, the acetylcholine input is lost and the glutamate neuron is released from GABA inhibition.

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

    Premisecitation

    The amyloid hypothesis is in doubt.

    “With the amyloid hypothesis in doubt (Holmes et al., 2008)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Holmes et al., 2008

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Silent desensitizers, which do not first activate ligand-gated ion channels, might also have low side-effect profiles.

    “Low sideeffect profiles also could be characteristic of silent desensitizers, which fail to first activate ligand-gated ion channel receptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Allosteric nAChR compounds show subtype specificity and may target specific subunit combinations and stoichiometries.

    “Not only do allosteric nAChR compounds exhibit subtype specificity, they could potentially be specific for various combinations and stoichiometries of subunits (Zwart et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zwart et al., 2008

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationown data

    The strong correlation raises the possibility that desensitization efficacy contributes to the cognitive-enhancing effects of these compounds.

    “the high degree of correlation between these two disparate responses to our test compounds at least suggests the possibility that efficacy for desensitization plays a role in the positive mnemonic responses produced by these compounds.”
    Quote in the paperSubstantial claim
30 of 30

  • The paper relies on this without support.

    Low microgram per kilogram doses of nicotine given to humans or nonhuman primates to improve cognition and working memory produce only low nanomolar brain concentrations.

    “Low microgram per kilogram doses of nicotine administered to humans or to nonhuman primates to improve cognition and working memory probably result only in low nanomolar brain concentra-tions-more in line with the ability of nicotine to induce receptor desensitization.”

  • The paper relies on this without support.

    The rat pressor-response desensitization assay is a valid predictor of working memory improvement in macaques.

    “The effectiveness of these four compounds in the task was linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation evoked by a nAChR agonist in rats.”

  • The authors state this as an assumption.

    Silent desensitizers act allosterically.

    “Because these”

  • The authors state this as an assumption.

    There is a direct relationship between the three systems: acetylcholine activates nicotinic receptors on GABA interneurons in the hippocampus, which inhibits primary hippocampal glutamate neurons.

    “It presumes that there is a direct relationship between the three systems; acetylcholine activates nicotinic receptors on GABA interneurons in the hippocampus, which in turn leads to inhibition of primary hippocampal glutamate neurons.”

  • The authors state this as an assumption.

    When acetylcholine is overactivated or a nAChR agonist is administered, the first response is further activation of the GABA interneuron.

    “When acetylcholine is overactivated (as with cholinesterase inhibitors) or when a nAChR agonist is administered, the first response is further activation of the GABA interneuron.”

  • The authors state this as an assumption.

    Because α7 nAChRs rapidly desensitize, the acetylcholine input is lost and the glutamate neuron is released from GABA inhibition.

    “However, because ␣7 nAChRs rapidly desensitize, the acetylcholine input is lost and the glutamate neuron is released from GABA inhibition (disinhibited).”
6 of 6

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?

  • 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).”

    From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Buccafusco et al., 2009

  • Nicotine and nAChR blockers may have comparable pharmacological/physiological effects.

    “Precedence for the idea that nAChR desensitization makes an important contribution to nicotine's functional effects is evident from previous work showing that nicotine and nAChR blockers may have comparable pharmacological/ physiological effects (Picciotto et al., 2008;Buccafusco et al., 2009).”

    From Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization (2010) · cites this paper as Buccafusco et al., 2009

  • Desensitization most likely involves post-translational receptor changes including receptor phosphorylation.

    “Desensitization most likely involves post-translational receptor changes including receptor phosphorylation (Corringer et al., 2006;Picciotto et al., 2008;Buccafusco et al., 2009).”

    From Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization (2010) · cites this paper as Buccafusco et al., 2009

  • Nicotine initially activates and then subsequently desensitizes or inactivates nAChRs, with a consequent receptor block.

    “The molecular basis for these seemingly discrepant observations may relate to findings that nicotine initially activates and then subsequently desensitizes or inactivates nAChRs, with a consequent receptor block (Corringer et al., 2006;Picciotto et al., 2008;Buccafusco et al., 2009).”

    From Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization (2010) · cites this paper as Buccafusco et al., 2009

  • Cotinine exhibits several nicotinelike properties, including effects on acoustic startle, attention, and neuroprotection.

    “Indeed, studies show that cotinine exhibits several nicotinelike properties, including effects on acoustic startle, attention, and neuroprotection (Buccafusco and Terry, 2003;Buccafusco et al., 2009).”

    From Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization (2010) · cites this paper as Buccafusco et al., 2009

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.

  • A cited d-tubocurarine study used cats, not rats

    Minor

    The text describes the cited fear-and-escape findings as occurring in rats, but the title of the cited Decsi and Karmos-Varszegi study specifies cats. The other citation in that sentence does concern rats.

  • The fourth tested compound has inconsistent identifiers

    Minor

    The DMPP study text calls the compound JWB2-22-33, while the caption for the same experiment calls it JAY2-22-33.

  • Two different structures are assigned to JWB1-84-1

    Minor

    The abstract identifies JWB1-84-1 with two different chemical names, apparently assigning the second compound's name to it as well.

3 of 3

Cites

Flagged first, then by citations

2 of the 41 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Buccafusco, J. J., Beach, J. W., & Terry, A. V.
Affiliations
  • Augusta University (US)
  • University of Georgia (US)
ORCID
Terry, Alvin V.
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2009-02
Volume
328
Issue
2
Pages
364-370
ISSN
0022-3565 (ISSN-L)
DOI
10.1124/jpet.108.145292
PMC
PMC2682277
OpenAlex
W2056125285
Semantic Scholar
42eebd75d35b57003fdf04a01f3073bd0101365e
Cited by
144
References
41
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 7 · 2017: 16 · 2016: 6 · 2015: 18 · 2014: 13 · 2013: 13 · 2012: 14
FWCI
4.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Drug Discovery Foundation
  • National Institutes of Health (n01mh32004-8-0-0)
  • Gillings School of Public Health
  • University of North Carolina at Chapel Hill
  • National Institute on Aging (R01AG029617)
  • National Institute of Mental Health (N01 MH032004)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
Keywords
nicotinic acetylcholine receptors, receptor desensitization, nicotine, cotinine, choline analogs, working memory, allosteric modulation, receptor subtypes, cognitive enhancement, drug development
MeSH terms
Allosteric Regulation, Animals, Binding Sites, Choline, Humans, Isoxazoles, Nicotine, Phenylurea Compounds, Piperazines, Pyridines, Receptors, Nicotinic, Drug Design, Nicotinic Agonists, Nicotinic Antagonists, 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