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Research ArticleNEUROPHARMACOLOGY

S33005, a Novel Ligand at Both Serotonin and Norepinephrine Transporters: I. Receptor Binding, Electrophysiological, and Neurochemical Profile in Comparison with Venlafaxine, Reboxetine, Citalopram, and Clomipramine

Mark J. Millan, Alain Gobert, Françoise Lejeune, Adrian Newman-Tancredi, Jean-Michel Rivet, Agnès Auclair and Jean-Louis Peglion
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 565-580;
Mark J. Millan
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Alain Gobert
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Françoise Lejeune
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Adrian Newman-Tancredi
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Jean-Michel Rivet
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Agnès Auclair
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Jean-Louis Peglion
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Abstract

S33005 displayed marked affinity for native, rat, and cloned human serotonin (5-HT) transporters (SERT) and less pronounced affinity for norepinephrine (NE) transporters (NET), while its affinity at dopamine (DA) transporters and >50 other sites was negligible. Reuptake of 5-HT and (less potently) NE into cerebral synaptosomes was inhibited by S33005, whereas DA reuptake was little affected. In vivo, S33005 prevented depletion of cerebral pools of 5-HT by parachloroamphetamine. Furthermore, it decreased electrical activity of raphe-localized serotonergic neurones, an action abolished by the 5-HT1A antagonist WAY100,635. At higher doses, S33005 blocked firing of locus ceruleus-localized adrenergic neurones, an action abolished by the α2-adrenergic antagonist idazoxan. In contrast, S33005 did not inhibit ventrotegmental dopaminergic neurones. In frontal cortex of freely moving rats, S33005 dose dependently elevated dialysate levels of 5-HT, NE,and DA. In hippocampus, levels of 5-HT and NE were similarly elevated, while in nucleus accumbens and striatum, levels of 5-HT were increased whereas DA was unaffected. Upon chronic (2 weeks) administration, basal levels of NE were elevated in frontal cortex and, therein, 5-HT2A receptor density was decreased. Comparative studies with clinically used antidepressants showed that venlafaxine possessed a profile similar to S33005 but was less potent. Clomipramine likewise interacted with SERTs and NETs but also with several other receptors types, while citalopram and reboxetine were preferential ligands of SERTs and NETs, respectively. In conclusion, S33005 interacts potently with SERTs and, less markedly, with NETs. It enhances extracellular levels of 5-HT and NE throughout corticolimbic structures and selectively elevates dialysis levels of DA in frontal cortex versus subcortical regions.

Footnotes

  • Abbreviations:
    5-HT
    serotonin
    AUC
    area under the curve
    AR
    adrenoceptor
    DA
    dopamine
    DAT
    dopamine transporter
    DRN
    dorsal raphe nucleus
    GBR12935
    1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine
    ANOVA
    analysis of variance
    CL
    confidence limit
    AP
    lateral
    L
    anteroposterior
    H
    height
    LC
    locus ceruleus
    NE
    norepinephrine
    NET
    norepinephrine transporter
    PCA
    parachloroamphetamine
    S33005
    (−)1-(1-dimethylaminomethyl) 5-methoxybenzocyclobutan-1-yl) cyclohexanol
    SERT
    serotonin transporter
    SSRI
    selective serotonin reuptake inhibitor
    WAY100,635
    N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo hexanecarboxamide
    VTA
    ventrotegmental area
    h
    human
    CHO
    Chinese hamster ovary
    M
    muscarinic
    • Received December 26, 2000.
    • Accepted March 29, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Research ArticleNEUROPHARMACOLOGY

S33005, a Novel Ligand at Both Serotonin and Norepinephrine Transporters: I. Receptor Binding, Electrophysiological, and Neurochemical Profile in Comparison with Venlafaxine, Reboxetine, Citalopram, and Clomipramine

Mark J. Millan, Alain Gobert, Françoise Lejeune, Adrian Newman-Tancredi, Jean-Michel Rivet, Agnès Auclair and Jean-Louis Peglion
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 565-580;

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Research ArticleNEUROPHARMACOLOGY

S33005, a Novel Ligand at Both Serotonin and Norepinephrine Transporters: I. Receptor Binding, Electrophysiological, and Neurochemical Profile in Comparison with Venlafaxine, Reboxetine, Citalopram, and Clomipramine

Mark J. Millan, Alain Gobert, Françoise Lejeune, Adrian Newman-Tancredi, Jean-Michel Rivet, Agnès Auclair and Jean-Louis Peglion
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 565-580;
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