Depressed patients suffer from cognitive dysfunction, including memory deficits. 
Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. 
The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 
5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A 
receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in 
normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 
2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved 
in its memory effects, and therefore investigated these effects in 5-HT depleted 
rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 
4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) 
induced 5-HT depletion, as measured in hippocampal homogenate and 
microdialysate. The effects of acute challenge with vortioxetine or the 5-HT 
releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and 
control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance 
were assessed along with the effects of acute treatment with 
5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake 
inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor 
duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA 
depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and 
SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At 
similar SERT occupancies (>90%) vortioxetine, but not escitalopram or 
duloxetine, restored memory performance. Acute fenfluramine significantly 
increased extracellular 5-HT in control and PCPA-treated rats, while 
vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT 
depletion impaired memory performance in rats through one or more of its 
receptor activities.