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

Jesper T Andreasen, John P Redrobe, Elsebet Ø Nielsen

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    38 Citationer (Scopus)

    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.

    OriginalsprogEngelsk
    TidsskriftPharmacology, Biochemistry and Behavior
    Vol/bind100
    Udgave nummer3
    Sider (fra-til)624-9
    Antal sider6
    ISSN0091-3057
    DOI
    StatusUdgivet - jan. 2012

    Emneord

    • Animals
    • Antidepressive Agents
    • Behavior, Animal
    • Benzamides
    • Bicyclo Compounds
    • Bicyclo Compounds, Heterocyclic
    • Cerebral Cortex
    • Citalopram
    • Depression
    • Disease Models, Animal
    • Dose-Response Relationship, Drug
    • Drug Synergism
    • Drug Therapy, Combination
    • Female
    • Mice
    • Mice, Inbred Strains
    • Molecular Targeted Therapy
    • Nicotinic Agonists
    • Receptors, Nicotinic
    • Serotonin
    • Serotonin Plasma Membrane Transport Proteins
    • Serotonin Uptake Inhibitors
    • Tissue Distribution
    • alpha7 Nicotinic Acetylcholine Receptor

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