Vortioxetine (Lu AA21004), a novel multimodal antidepressant, enhances memory in rats

Abstract

The serotonergic system plays an important role in cognitive functions via various 5-HT receptors. Vortioxetine (Lu AA21004) in development as a novel multimodal antidepressant is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist and a 5-HT transporter (5-HTT) inhibitor in vitro. Preclinical studies suggest that 5-HT3 and 5-HT7 receptor antagonism as well as 5-HT1A receptor agonism may have a positive impact on cognitive functions including memory. Thus vortioxetine may potentially enhance memory. We investigated preclinical effects of vortioxetine (1-10mg/kg administered subcutaneously [s.c.]) on memory in behavioral tests, and on cortical neurotransmitter levels considered important in rat memory function. Contextual fear conditioning and novel object recognition tests were applied to assess memory in rats. Microdialysis studies were conducted to measure extracellular neurotransmitter levels in the rat medial prefrontal cortex. Vortioxetine administered 1h before or immediately after acquisition of contextual fear conditioning led to an increase in freezing time during the retention test. This mnemonic effect was not related to changes in pain sensitivity as measured in the hotplate test. Rats treated with vortioxetine 1h before training spent more time exploring the novel object in the novel object recognition test. In microdialysis studies of the rat medial prefrontal cortex, vortioxetine increased extracellular levels of acetylcholine and histamine. In conclusion, vortioxetine enhanced contextual and episodic memory in rat behavioral models. Further demonstration of its potential effect on memory functions in clinical settings is warranted.

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

“…Additionally, vortioxetine was noted to increase ACh and HA levels in the medial prefrontal cortex. This is significant from a cognitive perspective as ACh is associated with learning and memory and HA is implicated in attention, vigilance and memory [11]. In several studies, rats were treated with a tryptophan hydroxylase inhibitor in order to deplete central 5-HT and consequently impair cognition.…”

“…The foregoing serotonergic actions are hypothesized to be relevant to the downstream modulation of other neurotransmitters implicated in mood and cognitive dysfunction, including NE, acetylcholine (ACh) and glutamate [7][8][9][10]. In preclinical studies, vortioxetine was found to increase extracellular levels of 5-HT, NE, ACh, HA and dopamine in brain regions relevant to mood and cognition [8,9,11].…”

Antidepresan İlaçların Öğrenme ve Bellek Mekanizmasına Etkileri

“…Sıçan medyal prefrontal kortekste mikrodiyaliz çalışmalarda, vortioksetin asetilkolin ve histamin hücre dışı seviyelerini arttırmıştır. Sonuç olarak, vortioksetin sıçan davranış modellerinde içeriksel ve epizodik bellekte iyileşmeler yaptığı görülmüştür 95 .…”

Cognitive impairment in depression and potential applications of antidepressants with procognitive effects

“…Это оз-начает, что он оказывает избирательный эффект на некоторые подтипы рецепторов серотониновой си-стемы. В частности, вортеоксетин является агони-стом 5-HT 1A -рецепторов, частичным агонистом 5-HT 1B -рецепторов и антагонистом 5-HT 1D -, 5-HT 3 -и 5-HT 7 -рецепторов [45,46]. Доклинические исследования показали, что во-ртеоксетин может увеличивать уровень серотонина, норадреналина и дофамина в префронтальной коре головного мозга, а также в гиппокампе крыс.…”

“…Доклинические исследования показали, что во-ртеоксетин может увеличивать уровень серотонина, норадреналина и дофамина в префронтальной коре головного мозга, а также в гиппокампе крыс. Кроме того, это препарат может повышать уровень ацетил-холина и гистамина, что соотносится с прокогни-тивным эффектом [46]. В ходе рандомизированного двойного слепого исследования эффективности применения ворти-оксетина, дулоксетина и плацебо [47] у пациентов позднего возраста было обнаружено, что как дулок-сетин, так и вортиоксетин статистически достовер-но улучшали выполнение теста на вербальное на-учение (Rey Auditory Verbal Learning Test) в сравне-нии с плацебо.…”