Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory Cécile Bétry a,1 , Adeline Etiévant a,1 , Alan Pehrson b , Connie Sánchez b , Nasser Haddjeri a, ⁎ a INSERM U846, Stem Cell and Brain Research Institute, Université Lyon 1, Lyon, F-69008, France b Neuropharmacological Research, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA abstract article info Article history: Received 11 September 2014 Received in revised form 1 December 2014 Accepted 8 December 2014 Available online 16 December 2014 Keywords: Antidepressant LTP Memory Neurogenesis Novel object recognition Vortioxetine Depression is frequently associated with cognitive disturbances. Vortioxetine is a multimodal acting antidepres- sant that functions as a 5-HT 3 and 5-HT 7 and 5-HT 1D receptor antagonist, 5-HT 1B receptor partial agonist, 5-HT 1A receptor agonist and inhibitor of the 5-HT transporter. Given its pharmacological profile, the present study was undertaken to determine whether vortioxetine could modulate several preclinical parameters known to be involved in cognitive processing. In the dorsal hippocampus of anaesthetized rats, the high-frequency stimulation of the Schaffer collaterals pro- voked a stable long-term potentiation (LTP) of ~25%. Interestingly, vortioxetine (10 mg/kg, i.p.) counteracted the suppressant effect of elevated platform stress on hippocampal LTP induction. In the novel object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this pro-cognitive effect was prevented by the partial 5-HT 3 receptor agonist SR57227 (1 mg/kg, i.p.). Finally, compared to fluoxetine, sustained administration of vortioxetine (5 mg/kg/day, s.c.) induced a rapid increase of cell proliferation in the hippocampal dentate gyrus. In summary, vortioxetine prevented the effect of stress on hippocampal LTP, increased rapidly hippocampal cell proliferation and enhanced short-term episodic memory, via, at least in part, its 5-HT 3 receptor antagonism. Taken together, these preclinical data suggest that the antidepressant vortioxetine may have a beneficial effect on human cognitive processes. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Major depressive disorder (MDD) is one of the most frequent psy- chiatric disorders. In the United States, the lifetime prevalence is more than 12% in men and 20% in women (Belmaker and Agam, 2008). MDD is an important public health problem since it results in severe dis- ability, poor quality of life and possibly suicide and is a major economic burden for society. Despite a range of pharmacotherapeutic options, treatment outcome remains unsatisfactory. Indeed, patients often need to try several different agents to obtain an effect and only about two thirds of patients experience a therapeutic response (Duman, 2004). In addition to a therapeutic delay of up to several weeks, a sig- nificant number of patients experience significant residual symptoms that are inadequately treated with current antidepressants (Conradi et al., 2011). Both preclinical (Henningsen et al., 2009; Kalueff and Murphy, 2007) and clinical (Baune et al., 2010; Hammar and Ardal, 2009) data suggest that affective disorders are often associated with dysfunction of different cognitive domains such as executive function, working memory and attention. Moreover, it has been shown that repeated episodes of major depression impair memory (Gorwood et al., 2008) and a correlation between depression severity and the magnitude of cognitive deficits has been reported in a population of young adult depressed patients (Basso and Bornstein, 1999; Egeland et al., 2003; Merriam et al., 1999). Also, antidepressant treatments often leave pa- tients with residual cognitive symptoms (Conradi et al., 2011). Thus, new antidepressants that alleviate cognitive dysfunction are clearly needed (Marazziti et al., 2010). Regulation of cognitive processes involves complex interaction be- tween many neurotransmitters among others serotonin. Preclinical studies have increased our understanding of the role of 5-HT and its re- ceptors in regulation of cognitive functions (Buhot, 1997; Buhot et al., 2000; King et al., 2008; Meneses, 2003; Meneses and Hong, 1997; Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 38–46 Abbreviations: 5-HT, 5-hydroxytryptamine, serotonin; vortioxetine, 1-[2-(2,4- dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004); LTP, long-term potentiation; SR57227, 1-(6-chloro-2-pyridinyl)-4-piperidinamine; MDD, major depressive disorder; SERT, 5-HT transporter; fEPSP, field excitatory post-synaptic potential; HFS, high- frequency stimulation; AUC, area under the curve; SGZ, subgranular zone; DG, dentate gyrus; BrDU, 5-bromo-2′-deoxyuridine; RI, recognition index; ANOVA, analysis of variance. ⁎ Corresponding author at: INSERM U846, Stem Cell and Brain Research Institute, Université Lyon 1, 8, Avenue Rockefeller 69373 Lyon Cedex 08 France. Tel.: +33 4 26 68 82 15; fax: +33 4 78 77 72 09. E-mail address: nasser.haddjeri@inserm.fr (N. Haddjeri). 1 CB and AE contributed equally to this work. http://dx.doi.org/10.1016/j.pnpbp.2014.12.002 0278-5846/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp