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 alpha2-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.
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.
M. Millan,A. Gobert,F. Lejeune,A. Newman-Tancredi,J. Rivet,A. Auclair,J. Peglion
Published 2001 in Journal of Pharmacology and Experimental Therapeutics
ABSTRACT
PUBLICATION RECORD
- Publication year
2001
- Venue
Journal of Pharmacology and Experimental Therapeutics
- Publication date
2001-08-01
- Fields of study
Medicine, Chemistry
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- cerebral synaptosomes
Isolated nerve-terminal brain preparations used to measure monoamine reuptake in vitro.
Aliases: synaptosomes
- citalopram
A clinically used antidepressant included as a comparator ligand in the study.
- clomipramine
A clinically used antidepressant included as a comparator ligand in the study.
- dopamine transporter
The membrane transporter responsible for dopamine reuptake that served as a comparison target in the binding and uptake assays.
Aliases: DAT
- frontal cortex
A rat brain region sampled for extracellular monoamine measurements and chronic treatment effects.
- hippocampus
A rat limbic brain region sampled for extracellular monoamine measurements after drug administration.
- norepinephrine transporter
The membrane transporter responsible for norepinephrine reuptake that was examined as a secondary target in the experiments.
Aliases: NET
- nucleus accumbens
A rat reward-related striatal region sampled for extracellular monoamine measurements after drug administration.
- reboxetine
A clinically used antidepressant included as a comparator ligand in the study.
- s33005
A synthetic ligand evaluated here in transporter binding, electrophysiological, and neurochemical assays.
- serotonin transporter
The membrane transporter responsible for serotonin reuptake that was a principal binding and functional target in the experiments.
Aliases: SERT
- striatum
A rat basal ganglia region sampled for extracellular monoamine measurements after drug administration.
- venlafaxine
A clinically used antidepressant included as a comparator ligand in the study.
REFERENCES
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