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Cited by 76Nicotinic Acetylcholine Receptors StudyTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

Cytisine-based nicotinic partial agonists as novel antidepressant compounds

Open access
Mineur, Yann S., Eibl, Christoph, Young, Grace, Kochevar, Christopher, Papke, Roger L., Gündisch, Daniela, Picciotto, Marina R.·2009·The Journal of Pharmacology and Experimental Therapeutics
DOI 10.1124/jpet.108.149609PMC PMC2670591
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Abstract

Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

Two cytisine derivatives were tested as nicotinic partial agonists; 3-pyr-Cyt was a low-efficacy α4β2 partial agonist with little activity at α3β4/α7 and produced antidepressant-like effects in mouse tail suspension, forced swim, and novelty-suppressed feeding tests. 5-Br-Cyt lacked peripheral behavioral effects but reduced immobility when given intracerebroventricularly, suggesting poor brain penetration.

Key findings

  • 3-pyr-Cyt was a weak partial agonist at α4β2 nAChRs (8% and 3% of ACh efficacy at LS and HS forms, respectively) and produced ≤5% ACh maximum activation of α3β4 or α7 receptors at concentrations ≤100 µM. 5-Br-Cyt was a partial agonist at α4β2 with approximately 16% efficacy of ACh and was more efficacious at α7 and α3β4 nAChRs.
  • Cytisine and 3-pyr-Cyt produced dose-dependent antidepressant-like effects in the tail suspension test and forced swim test, with 3-pyr-Cyt effective at lower concentrations than cytisine. In the tail suspension test, 3-pyr-Cyt was significant at 0.6 mg/kg (p = 0.012) and cytisine at 1 mg/kg (p = 0.004); in the forced swim test, 3-pyr-Cyt was significant at 0.3, 0.6, and 0.9 mg/kg (p = 0.015, p < 0.0001, p = 0.0014), and cytisine at 0.75 and 1 mg/kg (p = 0.014, p < 0.0001).
  • 5-Br-Cyt had no significant peripheral effect in the tail suspension test [F(4,44) = 0.58, p = 0.68] or forced swim test [F(4,40) = 1.80, p = 0.14], but centrally administered 5-Br-Cyt (50 ng i.c.v.) significantly reduced tail suspension immobility [F(1,14) = 6.14, p = 0.026].
  • Chronic (15 days) cytisine and 3-pyr-Cyt reduced latency to feed in the novelty-suppressed feeding test; the 3-pyr-Cyt effect was observed at only one dose and was relatively small. Acute nicotine had no significant effect versus saline in the tail suspension or forced swim tests, whereas fluoxetine reduced immobility in both tests (p = 0.026 and p = 0.034, respectively).

Methods

  • Cytisine derivatives were synthesized, characterized by radioligand binding, and tested electrophysiologically in Xenopus laevis oocytes expressing human nAChR clones or α4/β2 concatamers; responses were normalized to ACh controls and fit with the Hill equation.
  • Behavioral testing used 3-month-old male C57BL/6J mice (25–30 g), n = 10/group unless otherwise stated. Drugs were injected intraperitoneally 30 min before the tail suspension test (6 min) and forced swim test (15 min), separated by 48 h; then daily injections continued for 15 days before the novelty-suppressed feeding test. Locomotor activity was also measured, and 5-Br-Cyt was infused intracerebroventricularly (50 ng) in cannulated mice.
  • Behavioral data were analyzed with ANOVA using treatment and concentration as between-subject factors, followed by post hoc t tests with Bonferroni/Dunnett correction; α was set at 5%.

Limitations

  • Stated: whether the small efficacy differences at high- and low-sensitivity α4β2 receptors have measurable in vivo consequences remains unclear; it is not known whether the compounds are fully metabolized in 24 h, so carryover between tests is possible; and the 3-pyr-Cyt novelty-suppressed feeding effect was only at one dose and relatively small.
  • Stated/evident: the lack of peripheral 5-Br-Cyt effects is attributed to low brain penetration, but brain penetration was not directly measured; cytisine is also noted to have poor blood-brain barrier penetration.
  • Evident from the text: all behavioral data come from male C57BL/6J mice only, with sequential testing across paradigms, so sex, species, and test-order effects are not addressed.

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

Integrity signals

Registry

Crossref · 10.1124/jpet.108.149609

Cites

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Statistics

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Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Fluoxetine at 10 mg/kg significantly reduced immobility in the mouse forced swim test relative to saline.

    “however, fluoxetine resulted in a significant reduction of immobility at 10 mg/kg compared with saline-treated animals [F(1,16) ϭ 5.34, p ϭ 0.034; Fig. 4D].”
    Quote in the paperNot a substantial claim
  • Findingown data

    3-pyr-Cyt and 5-Br-Cyt were selected as selective partial agonists at α4β2 nAChRs.

    “Two compounds were selected that displayed selectivity as partial agonists of ␣4␤2 nAChRs: 3-pyr-Cyt (a pyridine-3-yl derivative) and 5-Br-Cyt.”
    Quote in the paperSubstantial claim
  • Findingown data

    There was a dose-dependent effect of cytisine on immobility in the tail suspension test.

    “There was a dose-dependent effect of 3-pyr-Cyt and cytisine but not 5-Br-Cyt on immobility in the tail suspension test [F(3,48) ϭ 3.18, p ϭ 0.032; F(3,47) ϭ 4.46, p ϭ 0.007; and F(4,44) ϭ 0.58, p ϭ 0.68, respectively; Fig. 3, A-C].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Rodent behavioral models of antidepressant efficacy predict antidepressant efficacy in humans.
    • Rests on an assumption: Immobility in the tail suspension and forced swim tests is a valid index of antidepressant-like activity.
    • Rests on an assumption: The antidepressant-like effects of the compounds at effective doses are not explained by altered locomotor activity.
  • Findingown data

    5-Br-Cyt efficiently reduced immobility in the tail suspension test when administered intraventricularly.

    “it efficiently reduced immobility in the tail suspension test when administered intraventricularly.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Immobility in the tail suspension and forced swim tests is a valid index of antidepressant-like activity.
  • Findingown data

    No effects on home-cage food intake or body weight were seen at any dose of cytisine, 3-pyr-Cyt, 5-Br-Cyt, or fluoxetine compared with saline-treated mice.

    “No effects on home-cage food consumption (5 min in home cage) or body weight were observed at any doses of cytisine, 3-pyr-Cyt, 5-Br-Cyt, or fluoxetine compared with saline-treated animals (data not shown).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Higher doses than those described were not well tolerated by mice and led to decreased locomotion, confounding behavioral testing.

    “we found that using higher doses than those described here were not well tolerated by the mice and led to decreased locomotion, confounding the outcome of behavioral testing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At both α4β2 receptor subtypes, 5-Br-Cyt lacked differential effects and had an average efficacy of roughly 18%, at least twice that of 3-pyr-Cyt.

    “5-Br-Cyt did not show differential effects at LS and HS nAChRs and had an average efficacy of ϳ18%, at least double that of 3-pyr-Cyt, at both receptor subtypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    3-pyr-Cyt is a relatively weak partial agonist for both LS and HS α4β2 receptors, with efficacy 8% and 3% of ACh, respectively, and similar potencies for both forms.

    “3-pyr-Cyt (Fig. 1C) is a relatively weak partial agonist for both the LS and HS receptors (efficacy 8 and 3%, respectively), with similar potencies for both forms of ␣4␤2 nAChRs (Fig. 1D).”
    • Also stated in: § Abstract · plain
      “3-pyr-Cyt was a partial agonist with very low efficacy at ␣4/␤2* nAChRS”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The α4β2 concatamer receptors used in oocytes accurately model native α4β2 nAChRs.

  • May combine two claims.

    Findingown data

    5-Br-Cyt showed no significant differences in activity at LS and HS forms of α4/β2 nAChRs and was a partial agonist with approximately 16% of ACh efficacy.

    “5-Br-Cyt (Fig. 1E), showed no significant differences in its activity at LS and HS forms of ␣4/␤2 nAChRs (Fig. 1F) and was a partial agonist with approximately 16% of the efficacy of ACh.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The α4β2 concatamer receptors used in oocytes accurately model native α4β2 nAChRs.

  • May combine two claims.

    Findingcitation

    Chronic cytisine treatment for 15 days, but not acute treatment, shortened the latency to begin feeding in the mouse novelty-suppressed feeding test relative to saline.

    “chronic (15 days), but not nAChR Partial Agonists and Depression acute, cytisine treatment decreased the latency to initiate feeding in the novelty-suppressed feeding test compared with saline treatment [F(2, 32) ϭ 2.42, p ϭ 0.01;”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mineur et al., 2007c

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Cytisine is a more efficacious partial agonist at low-sensitivity α4β2 nAChRs (about 10% of ACh) and a low-efficacy partial agonist at high-sensitivity α4β2 nAChRs (less than 5%).

    “cytisine was a more efficacious partial agonist at LS nAChRs (10% ACh) and a low-efficacy partial agonist at HS nAChRs (less than 5%) as has been shown previously (Bermudez and Moroni, 2006)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bermudez and Moroni, 2006

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the tail suspension test, 3-pyr-Cyt produced an antidepressant-like effect at lower concentrations than cytisine, while acute nicotine had no significant effects at any dose tested.

    “In the tail suspension test, 3-pyr-Cyt induced an antidepressant-like effect at lower concentrations than cytisine, whereas acute nicotine treatment had no significant effects at any of the doses tested.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    3-pyr-Cyt produced very little activation (≤5% ACh maximum) of α3β4 or α7 receptors at concentrations ≤100 μM, making it a weak partial agonist for all these neuronal nAChR subtypes.

    “3-pyr-Cyt (Fig. 2B) produced very little activation (Յ5% ACh maximum) of ␣3␤4 or ␣7 receptors at concentrations Յ100 M, making it a weak partial agonist for all of these neuronal nAChR subtypes.”
    • Also stated in: § Abstract · plain
      “had no agonist effects at other nAChRs normally targeted by cytisine”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The α4β2 concatamer receptors used in oocytes accurately model native α4β2 nAChRs.

  • May combine two claims.

    Findingown data

    In the forced swim test, cytisine at 0.75 and 1 mg/kg significantly lowered immobility in mice, but 1.5 mg/kg did not.

    “Mice treated with cytisine were significantly less immobile at doses of 0.75 and 1 mg/kg (p ϭ 0.014 and p Ͻ 0.0001, respectively), but this effect was not seen at 1.5 mg/kg.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mice, cytisine and 3-pyr-Cyt, but not 5-Br-Cyt, reduced immobility in the forced swim test in a dose-dependent manner.

    “Mice treated with cytisine or 3-pyr-Cyt, but not 5-Br-Cyt, showed a dose-dependent decrease in immobility in the forced swim test [F(3,44) ϭ 11.58, p Ͻ 0.0001; F(3,40) ϭ 10.51, p Ͻ 0.0001; and F(4,40) ϭ 1.80, p ϭ 0.14, respectively; Fig. 4, A-C].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    3-pyr-Cyt is a high-affinity, low-efficacy partial agonist at α4β2 nAChRs, with less than 10% activity relative to ACh.

    “3-pyr-Cyt was a high-affinity, low-efficacy partial agonist of ␣4␤2 nAChRS (Ͻ10% activity compared with ACh).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the novelty-suppressed feeding test, cytisine was active at concentrations similar to those in the tail suspension and forced swim tests, but 3-pyr-Cyt was effective only at a dose lower than those active in the other two tests.

    “Contrary to cytisine that showed an antidepressant-like effect in this test at concentration similar to those observed in both the tail suspension and the forced swim tests, 3-pyr-Cyt was only effective at a lower dose than those active in the two other tests.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    5-Br-Cyt had greater affinity than 3-pyr-Cyt for nAChR subtypes in binding assays and was a high-affinity, low-efficacy partial agonist at α4β2 nAChRs.

    “5-Br-Cyt, which had a greater affinity than 3-pyr-Cyt for nAChR subtypes in binding assays, and was a high-affinity, low-efficacy partial agonist at ␣4␤2 nAChRs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The effect of 3-pyr-Cyt in the novelty-suppressed feeding test was only observed at one dose and was relatively small.

    “This effect of 3-pyr-Cyt was only observed at one of the doses used, and the size of the effect was relatively small.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The study assessed the electrophysiological and antidepressant-like actions of two new cytisine derivatives, weak nicotinic partial agonists with greater selectivity and affinity for β2* nAChRs.

    “In summary, we have evaluated the electrophysiological and antidepressant-like effects of two new cytisine derivatives that are weak nicotinic partial agonists with greater selectivity and affinity for ␤2* nAChRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the current study, 3-pyr-Cyt modulated neither feeding nor body weight.

    “In the current study, 3-pyr-Cyt modulated neither feeding nor body weight (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cytisine and 3-pyr-Cyt both worked in the forced swim and tail suspension tests, but each was less potent in the tail suspension test.

    “Both cytisine and 3-pyr-Cyt were effective in the forced swim and tail suspension tests, although both compounds were less potent in the tail suspension test.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Mecamylamine can cause side effects including autonomic dysregulation, probably because it blocks ganglionic α3/β4* nAChRs.

    “mecamylamine can result in side effects, including dysregulation of the autonomic system, probably because of its ability to block ganglionic ␣3/␤4* nAChRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nicotine and other nicotinic agents can regulate mood in humans and have antidepressant-like effects in animal models.

    “Numerous studies have suggested that tobacco smoke can modulate depressive symptoms in human subjects and that nicotinic agents can have antidepressant-like effects in animal models (Picciotto et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Picciotto et al., 2002

      Not checked in the free run.

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

    Premisecitation

    Nicotine acts by binding to, activating, and desensitizing nAChRs in the CNS and autonomic ganglia.

    “Nicotine exerts its effects by binding to, activating, and desensitizing nicotinic acetylcholine receptors (nAChRs) in the central nervous system and autonomic ganglia (Picciotto et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Picciotto et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic nicotine administration can desensitize nAChRs, resulting in functional antagonism.

    “chronic nicotine administration can desensitize nAChRs (Reitstetter et al., 1999), resulting in functional antagonism (for reviews, see (Quick and Lester, 2002;Picciotto et al., 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Reitstetter et al., 1999

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    • cites Quick and Lester, 2002

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    • cites Picciotto et al., 2008

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

    Premisecitation

    In the peripheral nervous system, α3/β4* nAChRs are the main ganglionic subtype, but they are expressed at relatively low levels in the brain.

    “In the peripheral nervous system, ␣3/␤4* nAChRs are the main ganglionic subtype, but they are only expressed at relatively low levels in the brain (Gotti et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gotti et al., 2006

      Not checked in the free run.

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

    Premisecitation

    People with a history of depression have about a 50% higher smoking incidence than the general population.

    “Individuals with a history of depression have an approximately 50% higher incidence of smoking than the general population (Glassman et al., 1990).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Glassman et al., 1990

      Not checked in the free run.

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

    Premisecitation

    α7* nAChRs are found at high levels in brain, form functional homomers, and are highly expressed in hippocampus and cortex but also in most other brain regions.

    “whereas ␣7* nAChRs, which are also found at high levels in brain, form functional homomers and are highly expressed in the hippocampus and cortex but also found in most other brain regions (Zoli et al., 1998).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zoli et al., 1998

      Not checked in the free run.

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

    Study design and conductnone given

    During behavioral evaluation, experimenters were blinded to treatment.

    “During behavioral evaluation, the experimenters were blinded to treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cytisine is a partial agonist at β2* nAChRs and a full agonist at β4* nAChRs.

    “Cytisine is a partial agonist at ␤2* nAChRs and a full agonist at ␤4* nAChRs (Papke and Heinemann, 1994;Picciotto et al., 1995).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Papke and Heinemann, 1994

      Not checked in the free run.

    • cites Picciotto et al., 1995

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytisine is a full agonist at α3/β4* nAChRs at low concentrations, which results in autonomic activation and potential toxic side effects.

    “cytisine is a full agonist at ␣3/␤4* nAChRs at low concentrations, which results in autonomic activation and potential toxic side effects (Etter, 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Etter, 2006

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

    Premisecitation

    Nicotine was not used in the novelty-suppressed feeding test because it decreases appetite, confounding motivation to seek food.

    “Nicotine was not used in this test because it decreases appetite, confounding the motivation to seek food in the novelty-suppressed feeding test (Mineur et al., 2007c).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mineur et al., 2007c

      Not checked in the free run.

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

    Premisecitation

    C57BL/6J males are particularly resistant to stress, even chronic stressors.

    “C57BL/6J males are particularly resistant to stress, even chronic stressors (Mineur et al., 2006(Mineur et al., , 2007a)).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mineur et al., 2006

      Not checked in the free run.

    • cites Mineur et al., 2007a

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

    Study design and conductnone given

    After cannulation placement verification, seven control-treated and eight 5-Br-Cyt-treated animals were used for analysis.

    “After verification of placement, seven control-treated and eight 5-Br-Cyt-treated animals were used for subsequent analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    3-pyr-Cyt is a very weak partial nicotinic agonist at α4β2 nAChRs and has much less activity at α3β4 or α7 nAChRs than cytisine.

    “Taken together, these data indicate that 3-pyr-Cyt is a very weak partial nicotinic agonist at ␣4␤2 nAChRs with much less activity at ␣3␤4 or ␣7 nAChRs than cytisine.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The cytisine used here was synthesized in house rather than bought commercially as in earlier studies and may have been more purified and thus active at somewhat lower concentrations than previously.

    “The cytisine used in this study was synthesized in house rather than obtained commercially as in previous studies (Mineur et al., 2007c) and was potentially more purified and therefore active at somewhat lower concentrations than in the previous study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mineur et al., 2007c

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    In vivo, 3-pyr-Cyt acts like a competitive antagonist by competing with endogenous ACh and limiting α4β2*-dependent cholinergic signaling.

    “We hypothesize that in vivo, 3-pyr-Cyt competes with endogenous ACh, limiting ␣4␤2*-dependent cholinergic neurotransmission, similar to a competitive antagonist.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    α7 nAChRs may play a role in the response to antidepressants under specific conditions in C57BL/6J mice, because the effects of mecamylamine are abolished in α7 knockout mice.

    “␣7 nAChRs may also play a role in the response to antidepressants under specific conditions in C57BL/6J mice, because the effects of the nicotinic antagonist mecamylamine are abolished in ␣7 knockout mice (Rabenstein et al., 2006)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rabenstein et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    β4 null-mutant mice show reduced anxiety-like behavior in several paradigms, and activation of β4* nAChRs may be responsible for the ability of cytisine to increase anxiety-like behaviors.

    “Interestingly, ␤4 null-mutant mice show reduced anxietylike behavior in several paradigms (Salas et al., 2003) and activation of ␤4* nAChRs may be responsible for the ability of cytisine to increase anxiety-like behaviors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Salas et al., 2003

      Not checked in the free run.

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

    Interpretationreasoning

    The lack of behavioral effects observed with 5-Br-Cyt may be because of greatly reduced brain penetration.

    “Likewise, the lack of behavioral effects observed with 5-Br-Cyt may be because of greatly reduced brain penetration.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Nicotinic agents and cholinergic modulation are known to affect body temperature, likely through effects on the autonomic system such as vasoconstriction.

    “Nicotinic agents and cholinergic modulation are known to affect body temperature, likely through effects on the autonomic system such as vasoconstriction (Tritto et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tritto et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The inverted U-shaped dose response to cytisine and 3-pyr-Cyt in the forced swim test most likely reflects nonspecific harmful effects, since larger doses of nicotinic drugs tend to cause aversion and hypothermia, both of which would raise immobility.

    “The inverted Ushaped behavioral response to cytisine and 3-pyr-Cyt in the forced swim test is most likely because of nonspecific deleterious effects because higher doses of nicotinic agents tend to be aversive and hypothermic, two consequences that would increase immobility.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both nicotine and cytisine can decrease feeding and body weight.

    “For example, both nicotine (Jo et al., 2002) and cytisine (Mineur et al., 2007c) can decrease feeding and body weight.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jo et al., 2002

      Not checked in the free run.

    • cites Mineur et al., 2007c

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    3-pyr-Cyt may be more effective than cytisine in antidepressant tests because it is a low-efficacy partial agonist at both low- and high-sensitivity α4β2 nAChRs, whereas cytisine is a more effective agonist at low-sensitivity nAChRs.

    “3-pyr-Cyt may be more effective in tests of antidepressant action than cytisine because it is a low-efficacy partial agonist at both LS and HS ␣4␤2 nAChRs, whereas cytisine is a more effective agonist at LS nAChRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The novelty-suppressed feeding test responds only to chronic, not acute, classical antidepressants, so it is thought to capture neuronal adaptations underlying antidepressant effects in depressed humans, since patients need several weeks of treatment for benefit.

    “The novelty-suppressed feeding test is only sensitive to chronic, and not acute, treatment with classical antidepressants (Dulawa and Hen, 2005), and it is thus thought to be sensitive to the neuronal adaptations that result in antidepressant effects in human depressed patients, because antidepressants must be administered for several weeks in patients to be effective.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dulawa and Hen, 2005

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Although the tail suspension and forced swim tests share a similar principle as antidepressant efficacy screens, they rely on somewhat different behavioral variables.

    “Although the tail suspension and forced swim tests are both tests of antidepressant efficacy that are based on a similar principle (immobility in response to a stressor), the two tests are dependent on somewhat different behavioral variables.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Anxiety-like behavior could alter performance in the novelty-suppressed feeding test, and cytisine seems to be somewhat anxiogenic, potentially blunting the antidepressant-like effects measured in this paradigm.

    “Anxiety-like behavior could also alter performance in this test, and cytisine seems to be somewhat anxiogenic (Mineur et al., 2007c), potentially blunting the antidepressant like-effects measured in this paradigm.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mineur et al., 2007c

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The results do not reflect a failed study with 5-Br-Cyt because the tests were repeated on three independent groups of animals and no response was seen.

    “In addition, we are confident these results do not reflect a failed study with 5-Br-cyt because we repeated the tests on three independent groups of animals and never saw a response.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    3-pyr-Cyt should not activate α3β4 nAChRs to the same extent as cytisine; thus, if the anxiogenic effects of nicotinic agents involve this nAChR subtype, 3-pyr-Cyt may not increase anxiety-like behavior to the same extent as cytisine.

    “3-pyr-Cyt should not activate ␣3␤4 nAChRs to the same extent as cytisine, thus if the anxiogenic effects of nicotinic agents involve this nAChR subtype, 3-pyr-Cyt may not increase anxiety-like behavior to the same extent as cytisine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Many nicotinic agents can decrease feeding, which can be an important confound in the novelty-suppressed feeding paradigm.

    “Many nicotinic agents can decrease feeding, which can be an important confound in this paradigm.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jo et al., 2002

      Not checked in the free run.

    • cites Mineur et al., 2007c

      Not checked in the free run.

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

    Interpretationreasoning

    The tail suspension test is shorter than the forced swim test, which may give experimental compounds more time to alter behavior in the swim test and thus increase its sensitivity.

    “In addition, the tail suspension test is shorter in duration than the forced swim test, which may provide more time for the experimental compounds to alter behavior in the swim test, thus increasing its sensitivity.”
    Quote in the paperNot a substantial claim
47 of 47

  • The paper relies on this without support.

    Rodent behavioral models of antidepressant efficacy predict antidepressant efficacy in humans.

    “We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3Ј-yl)-cytisine (3pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests.”

  • The paper relies on this without support.

    Immobility in the tail suspension and forced swim tests is a valid index of antidepressant-like activity.

    “time spent immobile was recorded over a 6-min period”

  • The paper relies on this without support.

    The antidepressant-like effects of the compounds at effective doses are not explained by altered locomotor activity.

    “we found that using higher doses than those described here were not well tolerated by the mice and led to decreased locomotion, confounding the outcome of behavioral testing.”

  • The paper relies on this without support.

    The α4β2 concatamer receptors used in oocytes accurately model native α4β2 nAChRs.

    “we used a concatamer of the ␣4 and ␤2 subunits (Zhou et al., 2003) to force the formation either ␣4(2)␤2(3) receptors”

  • The paper relies on this without support.

    The mouse forced swim, tail suspension, and novelty-suppressed feeding tests are valid predictors of antidepressant efficacy in humans.

    “Both cytisine and 3-pyr-Cyt showed antidepressant-like effects in mice across three different models of antidepressant efficacy.”
    “suggest that fine tuning the pharmacology of nicotinic partial agonist may result in novel therapeutic compounds to treat mood disorders.”

  • The paper relies on this without support.

    The in vitro selectivity and efficacy of the compounds at nAChR subtypes translate to their in vivo behavioral effects.

    “This provides further evidence that blockade rather than activation of ␤2* nAChRs is responsible for the antidepressant-like effects of nicotinic agents (Caldarone et al., 2004;Rabenstein et al., 2006;Mineur et al., 2007c) because 3-pyr-Cyt had very low efficacy but high potency at ␣4␤2 nAChRs and low potency at both ␣3␤4 and ␣7 nAChRs.”
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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported effective cytisine dose was not among the administered doses

    Major

    The forced-swim results report an effect at 0.75 mg/kg, but the treatment protocol lists 0.6 mg/kg instead and does not list 0.75 mg/kg.

  • Figure 7 control-group size conflicts with verified animal count

    Minor

    The methods say seven control-treated animals remained after cannula-placement verification, but the figure caption reports eight animals per treatment group.

  • Figure 1 caption names the wrong receptor subtype

    Minor

    The caption calls the tested receptors α4β4, while its description of the high- and low-sensitivity forms identifies them as α4β2.

3 of 3

Cites

Flagged first, then by citations

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

Cited by

Sorted by citations

Related

Authors
Mineur, Y. S., Eibl, C., Young, G., Kochevar, C., Papke, R. L., Gündisch, D., & Picciotto, M. R.
Affiliations
  • Yale University (US)
  • University of Bonn (DE)
ORCID
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2009-04
Volume
329
Issue
1
Pages
377-386
ISSN
0022-3565 (ISSN-L)
DOI
10.1124/jpet.108.149609
PMC
PMC2670591
OpenAlex
W2116473479
Semantic Scholar
d012582a70f7eb31ee1be50bf8a0e2ea8ceafdab
Cited by
75
References
41
Citations by year
2026: 2 · 2025: 3 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 7 · 2014: 10 · 2013: 10 · 2012: 9
FWCI
3.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Florida
  • Deutsche Forschungsgemeinschaft
  • Rheinische Friedrich-Wilhelms-Universität Bonn
  • National Institutes of Health (DA00436)
  • National Institute of Mental Health (MH77681, R01MH077681)
  • National Institute on Drug Abuse (K02DA000436, DA 00436)
  • National Institute of General Medical Sciences (GM57481, R01GM057481)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
cytisine, nicotinic acetylcholine receptors, partial agonists, antidepressant-like effects, alpha7 nAChR, blood-brain barrier penetration, intraventricular administration, tail suspension test, forced swim test, mood disorders, nicotine
MeSH terms
Quinolizidine Alkaloids, Alkaloids, Animals, Antidepressive Agents, Azocines, Cloning, Molecular, Data Interpretation, Statistical, Electrophysiology, Environment, Feeding Behavior, Male, Mice, Inbred C57BL, Motor Activity, Oocytes, Quinolizines, Receptors, Cholinergic, Swimming, Xenopus laevis, Patch-Clamp Techniques, Nicotinic Agonists, Hindlimb Suspension, Laburnum, Mice

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.

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