Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation.

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.

Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism.

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (∼80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0µg/kg (∼25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (∼25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism.