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

Abstract

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.

Vortioxetine: a review of efficacy, safety and tolerability with a focus on cognitive symptoms in major depressive disorder

“…In several studies, rats were treated with a tryptophan hydroxylase inhibitor in order to deplete central 5-HT and consequently impair cognition. Vortioxetine demonstrated a reversal of this induced impairment in rats as assessed by the novel object recognition and Y-maze spontaneous alteration (spatial memory) tests [33,34]. The SSRI escitalopram and SNRI duloxetine, however, did not reverse any deficits [34].…”

“…The SSRI escitalopram and SNRI duloxetine, however, did not reverse any deficits [34]. Further, the beneficial effects in the object recognition task were maintained with chronic vortioxetine administration, but no improvement was noted in performance in the spontaneous alternation test [33]. With acute and subchronic vortioxetine administration, Wallace et al also showed reversal of induced cognitive impairment in rats using the attentional set-shifting test as a measure of reversal learning [35].…”

Estudo Do L-Triptofano Na Depressão Ocorrida Pela Doença De Alzheimer Em Modelos Experimentais

“…Para comprovar este pressuposto Du Jardin et al 27 realizaram um estudo em ratos adultos utilizando a paraclorofenilalanina, composto capaz de inibir o triptofano hidroxilase e por conseguinte diminuir a síntese de 5-HT. Com a redução do triptofano foi possível verificar que houve depleção da serotonina, observadas pelas alterações no teste de memória espacial no labirinto-Y e no reconhecimento de objetos.…”

“…Para a analgesia foi utilizado o cloridrato de tramadol na dose de 10 mg/kg diluído em 50ml de água, a cada 12 horas, por via oral, durante 7 dias 21 . Os animais ficaram em repouso por cinco dias e após esta data foram novamente anestesiados e levados ao estereotáxico onde receberam o peptídeo Beta-Amiloide [25][26][27][28][29][30][31][32][33][34][35] (Sigma-Aldrich) através de seringa de Hamilton na região hipocampica de CA1 conforme descrito por Freir, Costello e Herron 22 .…”

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

“…Ex vivo autoradiography data were quantified as described previously (du Jardin et al, 2014). Results are expressed as mean 6 S.E.M.…”