Differential inhibitory effects of drugs acting at the noradrenaline and 5-hydroxytryptamine transporters in rat and human neocortical synaptosomes.

British Journal of Pharmacology
M MantovaniT J Feuerstein

Abstract

Although the amino acid sequences of rat and human 5-hydroxytryptamine (5-HT) and noradrenaline (NA) transporters (i.e. SERT and NET) are highly homologous, species differences exist in the inhibitory effects of drugs acting at these transporters. Therefore, comparison of the potencies of drugs acting at SERT and NET in native human and rat neocortex may serve to more accurately predict their clinical profile. Synaptosomes prepared from fresh human and rat neocortical tissues were used for [(3)H]-5-HT and [(3)H]-NA saturation and competition uptake experiments. The drugs tested included NA reuptake inhibitors (desipramine, atomoxetine and (S,S)-reboxetine), 5-HT reuptake blockers (citalopram, fluoxetine and fluvoxamine) and dual 5-HT/NA reuptake inhibitors (duloxetine and milnacipran). In saturation experiments on synaptosomal [(3)H]-5-HT and [(3)H]-NA uptake, the dissociation constants did not indicate species differences although a smaller density of both SERT and NET was observed in human tissues. In competition experiments with the various drugs, marked species differences in their potencies were observed, especially at SERT. The rank order of selectivity ratios (SERT/NET) in human neocortex was as follows: citalopram >or= ...Continue Reading

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Citations

Apr 22, 1999·Immunology Today·J LloberasA Celada
Jun 12, 2012·Expert Opinion on Drug Discovery·Sonia Torres-SanchezEsther Berrocoso
Nov 21, 2012·The Journal of Surgical Research·Hassan AlbadawiMichael T Watkins
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May 29, 2014·Naunyn-Schmiedeberg's Archives of Pharmacology·Thomas J Feuerstein
Jan 17, 2017·Journal of Neural Transmission·Yoshikuni MizunoHideki Origasa
Jun 29, 2021·Frontiers in Cardiovascular Medicine·Thomas J Feuerstein, Eberhard Schlicker
Sep 3, 2010·Journal of Medicinal Chemistry·Bernard VacherMarc Marien

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