Vol. 298, Issue 2, 565-580, August 2001

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

Psychopharmacology Department (M.J.M., A.G., F.L., A.N.-T., J.-M.R., A.A.), Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France; and Medicinal Chemistry B Department (J.-L.P.), Institut de Recherches Servier, Centre de Recherche de Suresnes, Paris, France

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-HT_1A antagonist WAY100,635. At higher doses, S33005 blocked firing of locus ceruleus-localized adrenergic neurones, an action abolished by the ₂-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-HT_2A 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.