title: 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.
authors: Department of Synaptic Transmission 1, H. Lundbeck A/S, Ottiliavej 9, 2500 Copenhagen-Valby, Denmark. ARM@lundbeck.com
authors: Arne
authors: A
authors: Mørk
authors: Liliana P
authors: LP
authors: Montezinho
authors: Silke
authors: S
authors: Miller
authors: Crista
authors: C
authors: Trippodi-Murphy
authors: Niels
authors: N
authors: Plath
authors: Yan
authors: Y
authors: Li
authors: Maria
authors: M
authors: Gulinello
authors: Connie
authors: C
authors: Sanchez
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003214:Conditioning, Classical; D005239:Fear; D008297:Male; D008568:Memory / Q000187:drug effects*; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000494:pharmacology*; D000078784:Vortioxetine
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D013440:Sulfides; D000078784:Vortioxetine