Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests: A comparison of SSR180711 and PNU-282987

Andreasen, Jesper T.; Redrobe, John P.; Nielsen, Elsebet Ø.

doi:10.1016/j.pbb.2011.11.004

Cited by 44Nicotinic Acetylcholine Receptors StudyTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests: A comparison of SSR180711 and PNU-282987

Andreasen, Jesper T., Redrobe, John P., Nielsen, Elsebet Ø.·2012·Pharmacology Biochemistry and Behavior

DOI 10.1016/j.pbb.2011.11.004

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Abstract

Emerging evidence points to an involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. Nicotine improves symptoms of depression in humans and shows antidepressant-like effects in rodents. Monoamine release is facilitated by nAChR stimulation, and nicotine-evoked serotonin (5-HT) release has been shown to depend on α7 nAChR activation. The α7 nAChR agonist PNU-282987 shows no antidepressant-like activity when tested alone in the mouse forced swim (mFST) or tail suspension tests (mTST). However, in combination with a sub-active dose of the selective 5-HT reuptake inhibitor citalopram, inducing ~50% 5-HT reuptake inhibition, PNU-282987 has shown marked antidepressant-like effects in the mFST. SSR180711 is a recently described α7 nAChR agonist that has shown antidepressant-like activity in the rat forced swim test. To address the possibility that 5-HT reuptake inhibition contributes to the antidepressant-like profile of SSR180711, we compared the behavioural and biochemical profiles of PNU-282987 and SSR180711. In the mFST and mTST, SSR180711 (3-30 mg/kg, s.c.) showed dose-dependent antidepressant-like activity, while PNU-282987 (3-30 mg/kg, s.c.) showed no significant effect. The ED(50) to displace [³H]α-bungarotoxin binding was 1.7 and 5.5 mg/kg for SSR180711 and PNU-282987, respectively, suggesting that both compounds produce near-maximal α7 nAChR occupancy at the highest dose. While PNU-282987 did not affect ex vivo [³H]5-HT uptake, SSR180711 inhibited [³H]5-HT uptake with an ED₅₀ of 30 mg/kg. This degree of inhibition is similar to that observed with a citalopram dose of ~2.4 mg/kg, a dose that is normally not active in the mFST or mTST. This suggests that the antidepressant-like activity of SSR180711 may involve partial 5-HT reuptake inhibition. SSR180711 therefore represents a compound displaying the synergistic effect of α7 nAChR agonism combined with partial 5-HT reuptake inhibition previously described. The addition of α7 nAChR agonism to classical monoamine-based mechanisms may represent a novel option for the improved treatment of major depression.

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Increased signaling at α7 nAChRs in combination with therapies that increase serotonin signaling can improve performance in tests of antidepressant efficacy.
“increased signaling at α7 nAChRs in combination with therapies that increase serotonin signaling can also improve performance in tests of antidepressant efficacy (Andreasen et al., 2012; Andreasen et al., 2013)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Andreasen et al., 2012

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Authors: Andreasen, J. T., Redrobe, J. P., & Nielsen, E. Ø.
Affiliations: University of Copenhagen (DK)
Lundbeck (Denmark) (DK)
NeuroSearch (Denmark) (DK)
Corresponding author: Andreasen, Jesper T.
ORCID: Andreasen, Jesper T.
Venue: Pharmacology Biochemistry and Behavior
Publisher: Elsevier BV
Published: 2012-01
Volume: 100
Issue: 3
Pages: 624-629
ISSN: 0091-3057 (ISSN-L)
DOI: 10.1016/j.pbb.2011.11.004
OpenAlex: W1979579561
Cited by: 43
References: 53
Citations by year: 2026: 3 · 2025: 1 · 2024: 1 · 2023: 2 · 2021: 7 · 2019: 2 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 5 · 2012: 2
FWCI: 1.56
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Pharmacology Biochemistry and Behavior (publishedVersion)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
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: alpha7 nicotinic acetylcholine receptor, nicotinic agonists, PNU-282987, serotonin transporter inhibition, antidepressant-like effects, major depressive disorder, forced swim test, tail suspension test, citalopram, serotonin uptake, alpha-bungarotoxin binding, monoamine release, combination therapy
MeSH terms: Animals, Antidepressive Agents, Behavior, Animal, Benzamides, Bridged Bicyclo Compounds, Cerebral Cortex, Depression, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Synergism, Drug Therapy, Combination, Female, Mice, Inbred Strains, Receptors, Nicotinic, Serotonin, Tissue Distribution, Citalopram, Selective Serotonin Reuptake Inhibitors, Nicotinic Agonists, Bridged Bicyclo Compounds, Heterocyclic, Serotonin Plasma Membrane Transport Proteins, Mice, Molecular Targeted Therapy, alpha7 Nicotinic Acetylcholine Receptor

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Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests: A comparison of SSR180711 and PNU-282987

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