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Cited by 87Treatment of Major DepressionNicotinic Acetylcholine Receptors StudyNeurotransmitter Receptor Influence on Behavior

Varenicline has antidepressant-like activity in the forced swim test and augments sertraline's effect

Open access
Rollema, Hans, Guanowsky, Victor, Mineur, Yann S., Shrikhande, Alka, Coe, Jotham W., Seymour, Patricia A., Picciotto, Marina R.·2009·European Journal of Pharmacology
DOI 10.1016/j.ejphar.2009.01.002PMC PMC2707785
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Abstract

Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist developed as a smoking cessation aid, showed antidepressant-like activity in the forced swim test in two mouse strains. In addition, a low varenicline dose significantly enhanced the effects of moderately active doses of the selective serotonin reuptake inhibitor sertraline. These findings are consistent with the notion that reducing alpha4beta2 nicotinic acetylcholine receptor activity either by antagonists or by partial agonists that can partially activate or desensitize acetylcholine receptors is associated with antidepressant-like properties. These data suggest that varenicline may have antidepressant potential and can, when combined, augment antidepressant responses of selective serotonin reuptake inhibitors.

AI snapshot

Written from the paper’s full text.

TL;DR

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, reduced immobility in the mouse forced swim test in C57BL/6J and CD-1 strains and augmented sertraline’s antidepressant-like effect. Combining low-dose varenicline with sertraline produced amitriptyline-like reductions in swim score, suggesting potential antidepressant or adjunctive use pending clinical trials.

Key findings

  • Varenicline significantly reduced immobility in both mouse strains at most doses tested: C57BL/6J mice at 0.25–1.5 mg/kg i.p. and CD-1 mice at 0.178–5.6 mg/kg i.p.; the effect size was greater in C57BL/6J than in CD-1 mice.
  • In CD-1 mice, varenicline at doses of 5.6 mg/kg and above produced swim scores comparable to sertraline, while amitriptyline at 10 mg/kg reduced immobility with greater efficacy than varenicline or sertraline alone.
  • Co-administration of varenicline and sertraline reduced swim scores more than the corresponding sertraline doses alone; 0.56 mg/kg varenicline plus 17.8 mg/kg sertraline had the same pronounced effect as 10 mg/kg amitriptyline.
  • Low effective doses were consistent with varenicline’s high α4β2 binding affinity (Ki = 0.15 nM), inactivating potency (IC50 = 6 nM), and 45% agonist activity relative to nicotine.

Methods

  • Forced swim test experiments were performed in male C57BL/6J mice at Yale University and male CD-1 mice at Pfizer Inc.; mice were 14–16 weeks old and weighed 30–35 grams. Varenicline was administered i.p., sertraline s.c., and amitriptyline s.c., with pretreatment times of 30–60 min.
  • C57BL/6J mice were placed in 15 cm deep water (~25 °C) 30 min after dosing, and immobility was recorded over 15 min (n = 10 per treatment), analyzed by ANOVA. CD-1 mice were placed in 10 cm deep water (23–25 °C) 60 min after dosing, scored every 30 seconds over 5 min as immobile or active (total score 0–10; n = 10–30 per treatment), and analyzed with Kruskal–Wallis followed by Bonferroni-corrected Mann–Whitney U tests.
  • Test compounds were also assessed for effects on spontaneous locomotor activity; at the doses used for the forced swim test, none increased locomotor activity.

Limitations

  • The paper states that inactive doses were not obtained in either study and a clear dose-response relationship was not demonstrated, so further studies are necessary to define responses at the low end of the dose range.
  • The paper states that strain differences and differences in monitoring times and scoring methods could contribute to the observed effect sizes in each forced swim test protocol.
  • Evident from the text: these are preclinical mouse forced swim test findings only; the paper explicitly says future clinical trials are needed to confirm the data and assess whether the forced swim test’s predictive validity extends beyond monoamine-based classical antidepressants.

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

Integrity signals

Registry

Crossref · 10.1016/j.ejphar.2009.01.002

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 22 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Varenicline showed antidepressant-like activity in the forced swim test in two mouse strains.

    “Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist developed as a smoking cessation aid, showed antidepressant-like activity in the forced swim test in two mouse strains.”
    • Also stated in: § 3. Results · plain
      “Varenicline significantly reduced immobility in both mouse strains at most doses tested (Fig. 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    A low varenicline dose significantly enhanced the effects of moderately active doses of the SSRI sertraline.

    “In addition, a low varenicline dose significantly enhanced the effects of moderately active doses of the selective serotonin reuptake inhibitor sertraline.”
    • Also stated in: § 3. Results · plain
      “Co-administration of varenicline and sertraline resulted in lower swim scores than after each sertraline dose alone.”
    • Also stated in: § 3. Results · plain
      “Combining 0.56 and 5.6 mg/kg of varenicline with the lowest (1.78 mg/kg) and highest (17.8 mg/kg) sertraline dose, respectively, reduced the swim score significantly more than the corresponding sertraline doses alone.”
    Quote in the paperSubstantial claim
  • Findingown data

    Varenicline administration results in comparable swim scores as the SSRI sertraline at doses of 5.6 mg/kg and above in CD-1 mice.

    “A comparison with the effects of the classical antidepressants amitriptyline and sertraline in CD-1 mice shows that varenicline administration results in comparable swim scores as the SSRI sertraline at doses of 5.6 mg/kg and above (Fig. 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    At 10 mg/kg, amitriptyline reduced immobility scores with greater efficacy than varenicline or sertraline when given alone in CD-1 mice.

    “At 10 mg/kg, the tricyclic antidepressant amitriptyline, which consistently yields pronounced dose-dependency and near maximal efficacy in dose-response studies (data not shown; see e.g. Caldarone et al, 2004), reduced immobility scores with greater efficacy than varenicline or sertraline when given alone (Fig. 1B).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Caldarone et al, 2004 source

      Not checked in the free run.

  • Findingnone given

    The forced swim test data for varenicline generated in each laboratory in different mouse strains are in good agreement, despite variations in the protocols.

    “The forced swim test data for varenicline generated in each laboratory in different mouse strains are thus in good agreement, despite variations in the protocols.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 7
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    The response to varenicline in CD-1 mice was comparable to that of sertraline in terms of effect size and dose-response relationship.

    “The effect size in C57BL/6J mice (0.25–1.5 mg/kg i.p., Fig. 1A) was greater than in CD-1 mice (0.178 – 5.6 mg/kg i.p., Fig. 1B), with the response in the latter strain being comparable to that of sertraline in terms of effect size and dose-response relationship (sertraline data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neuronal nicotinic acetylcholine receptor antagonists and partial agonists may have utility in the treatment of depression, either alone or combined with antidepressants.

    “Neuronal nicotinic acetylcholine receptor antagonists and partial agonists may have utility in the treatment of depression, either alone or combined with antidepressants (Shytle et al, 2003; Picciotto et al, 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Shytle et al, 2003

      Not checked in the free run.

    • cites Picciotto et al, 2008 source

      Not checked in the free run.

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

    Premisecitation

    A recent study confirmed antidepressant-like properties of mecamylamine, but found that a full agonist of α4β2 and an agonist or antagonist of α7 lacked efficacy in the forced swim test and tail suspension test.

    “A recent study confirmed the antidepressant-like properties of mecamylamine, but found that a full agonist of the α4β2 subtype and an agonist or antagonist of the α7 subtype lacked efficacy in the forced swim test and the tail suspension test (Andreasen et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Andreasen et al., 2008

      Not checked in the free run.

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

    Interpretationcitation

    Strain differences could account for variations in the degree of efficacy in these forced swim test studies.

    “Strain differences could account for variations in the degree of efficacy in these forced swim test studies and are well-documented for several mouse behavioral responses (e.g. Mineur et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mineur et al., 2006 source

      Not checked in the free run.

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

    Premisecitation

    Varenicline can potently desensitize α4β2 nicotinic acetylcholine receptors with an IC50 value of 6 nM for inhibiting nicotine-evoked currents.

    “Varenicline has at least 100-fold higher affinity for α4β2 than for other subtypes, is a 45% agonist as compared with nicotine and can potently desensitize α4β2 nicotinic acetylcholine receptors with an IC50 value of 6 nM for inhibiting nicotine-evoked currents (Rollema et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rollema et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The present results are in agreement with previous reports that both nicotinic acetylcholine receptor antagonists and partial agonists show antidepressant-like efficacy in animal depression models and can also increase antidepressant activity when co-administered with classic antidepressants such as SSRIs or tricyclic antidepressants.

    “The present results are in agreement with previous reports that both nicotinic acetylcholine receptor antagonists and partial agonists show antidepressant-like efficacy in animal depression models and can also increase antidepressant activity when co-administered with classic antidepressants such as SSRIs or tricyclic antidepressants (Caldarone et al., 2004; Rabenstein et al., 2006; Mineur et al.,”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Caldarone et al., 2004 source

      Not checked in the free run.

    • cites Rabenstein et al., 2006 source

      Not checked in the free run.

    • cites Mineur et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Varenicline may have potential as an antidepressant, either alone or as an augmentation strategy for depression in combination with classical antidepressants.

    “These preclinical data therefore suggest that varenicline may have potential as an antidepressant, either alone or, given its ability to amplify the SSRI response, as an augmentation strategy for depression in combination with classical antidepressants.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The forced swim test has good predictive validity for antidepressant activity.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The study tested the compounds for effects on spontaneous locomotor activity to control for potential confounding of forced swim test data.

    “Since drug-induced changes in locomotor activity can confound the interpretation of forced swim test data, the test compounds were also tested for effects on spontaneous locomotor activity in locomotor activity chambers.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Varenicline is a 45% agonist as compared with nicotine.

    “Varenicline has at least 100-fold higher affinity for α4β2 than for other subtypes, is a 45% agonist as compared with nicotine and can potently desensitize α4β2 nicotinic acetylcholine receptors with an IC50 value of 6 nM for inhibiting nicotine-evoked currents (Rollema et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rollema et al., 2007 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Varenicline has at least 100-fold higher affinity for α4β2 than for other subtypes.

    “Varenicline has at least 100-fold higher affinity for α4β2 than for other subtypes, is a 45% agonist as compared with nicotine and can potently desensitize α4β2 nicotinic acetylcholine receptors with an IC50 value of 6 nM for inhibiting nicotine-evoked currents (Rollema et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rollema et al., 2007 source

      Not checked in the free run.

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

    Interpretationreasoning

    A lack of dose-dependency of the forced swim test effects may suggest that once a dose of the partial agonist is administered that is sufficient to reduce endogenous ACh signaling or that achieves maximum receptor occupancy, the response will remain the same over a wide dose range, resulting in a plateauing of the effect.

    “A lack of dose-dependency of the forced swim test effects may suggest that once a dose of the partial agonist is administered that is sufficient to reduce endogenous ACh signaling or that achieves maximum receptor occupancy, the response will remain the same over a wide dose range, resulting in a plateauing of the effect.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Partial agonists can modulate ACh signaling not only via decreased efficacy at the receptor, but also via inactivating nicotinic acetylcholine receptors by desensitization.

    “Partial agonists can modulate ACh signaling not only via their decreased efficacy at the receptor, but also via inactivating nicotinic acetylcholine receptors by desensitization (Hogg and Bertrand, 2007; Picciotto et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hogg and Bertrand, 2007

      Not checked in the free run.

    • cites Picciotto et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Inactive doses were not obtained in either study and a clear dose-response relationship was not demonstrated.

    “Since inactive doses were not obtained in either of the studies and a clear dose-response relationship was not demonstrated, further studies will be necessary to define the responses at the low end of the dose range.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Differences in monitoring times and scoring methods could contribute to the observed effect sizes in each method.

    “In addition, differences in monitoring times and scoring methods could also contribute to the observed effect sizes in each method.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The fact that low doses of varenicline have significant effects in both experiments is consistent with varenicline's high in vitro binding affinity and inactivating potency at α4β2 nicotinic acetylcholine receptors, as well as with its potent activity in in vivo models.

    “The fact that low doses of varenicline (i.e. 0.25 mg/kg in C57BL/6J mice and 0.178 mg/kg in CD-1 mice) have significant effects in both experiments is consistent with varenicline’s high in vitro binding affinity (Ki = 0.15 nM) and inactivating potency (IC50 = 6 nM) at α4β2 nicotinic acetylcholine receptors, as well as with its potent activity in in vivo models, such as increasing mesolimbic”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rollema et al., 2007 source

      Not checked in the free run.

15 of 15

  • The paper relies on this without support.

    The forced swim test has good predictive validity for antidepressant activity.

    “This study provides evidence that varenicline, the first nicotinic acetylcholine receptor ligand approved for pharmacotherapeutic use (as Chantix or Champix), has activity in an animal model that has good predictive validity for antidepressant activity.”
    “Preclinical studies in the forced swim test and the tail suspension test, established mouse models of antidepressant efficacy, have demonstrated antidepressant-like activity of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine and the selective α4β2 nicotinic acetylcholine receptor partial agonists, cytisine (Caldarone et al., 2004; Rabenstein et al., 2006; Mineur et al.,”
1 of 1

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?

  • Nicotinic partial agonists are effective in mouse models of antidepressant efficacy.

    “nicotinic partial agonists, that would be expected to decrease activity of acetylcholine at endogenous nAChRs when cholinergic tone is high but increase activity of nAChRs when cholinergic tone is low, are effective in mouse models of antidepressant efficacy (Mineur et al. 2007(Mineur et al. , 2009b(Mineur et al. , 2011a;;Rollema et al. 2009;Caldarone et al. 2011)”

    From Mechanisms of Nicotine Addiction (2021) · cites this paper as Rollema et al. 2009

  • The effects of SSRIs and NRIs in models of depression-like behaviors can be potentiated by nAChR antagonists or partial agonists.

    “the effects of selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs) in models of depression-like behaviors can be potentiated by nAChR antagonists or partial agonists”

    From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Rollema et al., 2009

  • The discrepancy between Rollema et al. (2009) and Turner et al. (2010) results is likely due to the different mouse strains used, C57BL/6J and 129SvJ-C57BL/6J F1 hybrid mice.

    “The discrepancy between Rollema et al. (2009) and Turner et al. (2010) results is likely to be due to the different mouse strains used by these two studies, C57BL/6J mice and 129SvJ-C57BL/6J F1 hybrid mice, respectively.”

    From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Rollema et al., 2009

  • Varenicline, a partial agonist of α4β2 nAChRs and a full α7 agonist developed to aid smoking cessation, has antidepressant effects in the forced swim test.

    “varenicline, a partial agonist of the α4β2 nAChRs and a full α7 agonist developed to aid smoking cessation in humans (Mihalak, Carroll, & Luetje, 2006), has also been found to have antidepressant effects in the FST (Rollema et al., 2009).”

    From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Rollema 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.

  • Hogg and Bertrand citation year differs

    Minor

    The conclusion cites Hogg and Bertrand as a 2005 source, but the paper's reference list identifies their cited work as published in 2007.

1 of 1

The citation lists haven’t been fetched yet

References 16 · Cited by 87

Authors
Rollema, H., Guanowsky, V., Mineur, Y. S., Shrikhande, A., Coe, J. W., Seymour, P. A., & Picciotto, M. R.
Affiliations
  • Pfizer (United States) (US)
  • Yale University (US)
Corresponding author
Rollema, Hans
ORCID
Venue
European Journal of Pharmacology
Publisher
Elsevier BV
Published
2009-03
Volume
605
Issue
1-3
Pages
114-116
ISSN
0014-2999 (ISSN-L)
DOI
10.1016/j.ejphar.2009.01.002
PMC
PMC2707785
OpenAlex
W1972510096
Cited by
87
References
16
Citations by year
2026: 3 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 3 · 2018: 2 · 2017: 4 · 2016: 6 · 2015: 9 · 2014: 9 · 2013: 9 · 2012: 10
FWCI
8.39
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Pfizer
  • National Institutes of Health (DA00436, MH077681)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
varenicline, antidepressant-like effects, forced swim test, sertraline, selective serotonin reuptake inhibitors, α4β2 nicotinic acetylcholine receptor, partial agonists, drug augmentation, depression, smoking cessation
MeSH terms
Varenicline, Animals, Antidepressive Agents, Benzazepines, Depression, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Synergism, Mice, Inbred C57BL, Mice, Inbred ICR, Quinoxalines, Receptors, Nicotinic, Swimming, Selective Serotonin Reuptake Inhibitors, Nicotinic Agonists, Sertraline, Mice

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