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.