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Research ArticleNeuropharmacology

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: II. A Behavioral, Neurochemical, and Electrophysiological Characterization

Anne Dekeyne, Mauricette Brocco, Florence Loiseau, Alain Gobert, Jean-Michel Rivet, Benjamin Di Cara, Thomas I. Cremers, Gunnar Flik, Kevin C. F. Fone, David J. G. Watson, Mariusz Papp, Trevor Sharp, Florence Serres, Raymond Cespuglio, Berend Olivier, Johnny S. W. Chan, Gilbert Lavielle and Mark J. Millan
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 765-780; DOI: https://doi.org/10.1124/jpet.111.187534
Anne Dekeyne
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Mauricette Brocco
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Florence Loiseau
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Alain Gobert
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Jean-Michel Rivet
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Benjamin Di Cara
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Thomas I. Cremers
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Gunnar Flik
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Kevin C. F. Fone
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David J. G. Watson
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Mariusz Papp
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Trevor Sharp
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Florence Serres
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Raymond Cespuglio
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Berend Olivier
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Johnny S. W. Chan
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Gilbert Lavielle
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Mark J. Millan
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Abstract

The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)2C receptor inverse agonist and α2-adrenoceptor antagonist that also possesses 5-HT2A antagonist properties (J Pharmacol Exp Ther 340:750–764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63–40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by “promnemonic” properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.187534.

  • ABBREVIATIONS:

    S32212
    N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide)
    5-HT
    serotonin
    ACh
    acetylcholine
    AR
    adrenoceptor
    BDNF
    brain-derived neurotrophic factor
    CMS
    chronic mild stress
    DA
    dopamine
    DRN
    dorsal raphe nucleus
    EEG
    electroencephalogram
    EMG
    electromyogram
    FCX
    frontal cortex
    LC
    locus coeruleus
    LRR
    loss of righting reflex
    MED
    minimal effective dose
    NA
    noradrenaline
    NOR
    novel object recognition
    REM
    rapid eye movement
    SND
    social novelty discrimination
    SSRI
    selective serotonin reuptake inhibitor
    SWS
    slow-wave sleep
    VTA
    ventral tegmental area
    ANOVA
    analysis of variance
    AP
    anteroposterior
    ML
    mediolateral
    DV
    dorsoventral
    HPLC
    high-performance liquid chromatography
    T1
    first 5-min session
    T2
    second 5-min session
    P1
    first 5-min period
    P2
    second 5-min period
    AUC
    area under the curve
    S18616
    (S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2′-(1′,2′,3′,4′-tetrahydronaphthalene)].

  • Received September 30, 2011.
  • Accepted November 29, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleNeuropharmacology

5-HT2C Receptors, α2-Adrenoceptors, and Depression

Anne Dekeyne, Mauricette Brocco, Florence Loiseau, Alain Gobert, Jean-Michel Rivet, Benjamin Di Cara, Thomas I. Cremers, Gunnar Flik, Kevin C. F. Fone, David J. G. Watson, Mariusz Papp, Trevor Sharp, Florence Serres, Raymond Cespuglio, Berend Olivier, Johnny S. W. Chan, Gilbert Lavielle and Mark J. Millan
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 765-780; DOI: https://doi.org/10.1124/jpet.111.187534

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Research ArticleNeuropharmacology

5-HT2C Receptors, α2-Adrenoceptors, and Depression

Anne Dekeyne, Mauricette Brocco, Florence Loiseau, Alain Gobert, Jean-Michel Rivet, Benjamin Di Cara, Thomas I. Cremers, Gunnar Flik, Kevin C. F. Fone, David J. G. Watson, Mariusz Papp, Trevor Sharp, Florence Serres, Raymond Cespuglio, Berend Olivier, Johnny S. W. Chan, Gilbert Lavielle and Mark J. Millan
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 765-780; DOI: https://doi.org/10.1124/jpet.111.187534
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