Vortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism

Daniela Felice, Jean-Philippe Guilloux, Alan Pehrson, Yan Li, Indira Mendez-David, Alain M Gardier, Connie Sanchez, Denis J David, Daniela Felice, Jean-Philippe Guilloux, Alan Pehrson, Yan Li, Indira Mendez-David, Alain M Gardier, Connie Sanchez, Denis J David

Abstract

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT's effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.

Keywords: c-Fos; context discrimination; mice; neurogenesis; vortioxetine.

Figures

FIGURE 1
FIGURE 1
Experimental protocol.
FIGURE 2
FIGURE 2
Effects of VORT (1.8 g/kg; ∼10 mg/kg) treatment on CD in C57BL/6J Rj mice. Two-way repeated measures ANOVA of context and day followed by Fisher’s predicted least-square difference post hoc tests; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001 (A,B: context A versus context B; C: VEH versus VORT). The n number for CD protocol was: vehicle (VEH), n = 10; Vortioxetine (VORT), n = 10.
FIGURE 3
FIGURE 3
Effects of ablation of adult hippocampal neurogenesis on context discrimination in VEH and VORT (1.8 g/kg; ∼10 mg/kg) treated GFAP-TK TG mice. Two-way repeated measures ANOVA of context and day followed by Fisher’s predicted least-square difference post hoc tests; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001 (A–D: context A versus context B; E: GCV/VEH versus GCV/VORT). The n number for CD protocol was: NON-GCV/VEH, n = 10; GCV/VEH, n = 9; NON-GCV/VORT, n = 8; GCV/VORT, n = 7. GFAP-TK TG mice, glial fibrillary acidic protein (GFAP)-Thymidine kinase (TK) engineered male; GCV, Ganciclovir; VEH, vehicle; VORT, Vortioxetine.
FIGURE 4
FIGURE 4
Effects of VORT treatment on freezing behavior in VEH and VORT (1.8 g/kg; ∼10 mg/kg) treated mice. Unpaired two-tailed student’s t-tests between VEH and VORT group or Two-way repeated measures ANOVA of context and day followed by Fisher’s predicted least-square difference post hoc tests; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001 (A–D: VEH versus VORT; E: VEH versus GCV/VEH; F: VORT versus GCV/VORT). GFAP-TK TG mice, glial fibrillary acidic protein (GFAP)-Thymidine kinase (TK) engineered male; GCV, Ganciclovir; VEH, vehicle; VORT, Vortioxetine.
FIGURE 5
FIGURE 5
Effects of VORT (1.8 g/kg; ∼10 mg/kg) treatment on shock-induced c-Fos activation in the adult hippocampus in C57BL/6J Rj mice (Dorsal hippocampus, A–D; Ventral hippocampus, E–H). Unpaired two-tailed student’s t-tests between VEH and VORT group; ∗∗p < 0.01. VEH, vehicle; VORT, Vortioxetine.
FIGURE 6
FIGURE 6
Effects of VORT (1.8 g/kg; ∼10 mg/kg) treatment on shock-induced c-Fos activation in the adult hippocampus (Total DG, A; Dorsal DG, B; Ventral DG, C) in GFAP-TK TG mice. GFAP-TK TG mice, glial fibrillary acidic protein (GFAP)-Thymidine kinase (TK) engineered male; GCV, Ganciclovir; VEH, vehicle; VORT, Vortioxetine.

References

    1. Al-Sukhni M., Maruschak N. A., McIntyre R. S. (2015). Vortioxetine : a review of efficacy, safety and tolerability with a focus on cognitive symptoms in major depressive disorder. Expert Opin. Drug Saf. 14 1291–1304. 10.1517/14740338.2015.1046836
    1. Amado-Boccara I., Gougoulis N., Poirier Littre M. F., Galinowski A., Loo H. (1995). Effects of antidepressants on cognitive functions: a review. Neurosci. Biobehav. Rev. 19 479–493. 10.1016/0149-7634(94)00068-C
    1. Austin M. P., Mitchell P., Goodwin G. M. (2001). Cognitive deficits in depression: possible implications for functional neuropathology. Br. J. Psychiatry 178 200–206. 10.1192/bjp.178.3.200
    1. Bannerman D. M., Rawlins J. N., McHugh S. B., Deacon R. M., Yee B. K., Bast T., et al. (2004). Regional dissociations within the hippocampus–memory and anxiety. Neurosci. Biobehav. Rev. 28 273–283. 10.1016/j.neubiorev.2004.03.004
    1. Bannerman D. M., Yee B. K., Good M. A., Heupel M. J., Iversen S. D., Rawlins J. N. (1999). Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions. Behav. Neurosci. 113 1170–1188. 10.1037/0735-7044.113.6.1170
    1. Becker S. (2016). Neurogenesis and pattern separation: time for a divorce. Wiley Interdiscip. Rev. Cogn. Sci. 8:e1427. 10.1002/wcs.1427
    1. Betry C., Etievant A., Pehrson A., Sanchez C., Haddjeri N. (2015). Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory. Prog. Neuropsychopharmacol. Biol. Psychiatry 58 38–46. 10.1016/j.pnpbp.2014.12.002
    1. Brooks S. P., Pask T., Jones L., Dunnett S. B. (2005). Behavioural profiles of inbred mouse strains used as transgenic backgrounds. II: cognitive tests. Genes Brain Behav. 4 307–317. 10.1111/j.1601-183X.2004.00109.x
    1. Clelland C. D., Choi M., Romberg C., Clemenson G. D., Jr., Fragniere A., Tyers P., et al. (2009). A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325 210–213. 10.1126/science.1173215
    1. Danielson N. B., Kaifosh P., Zaremba J. D., Lovett-Barron M., Tsai J., Denny C. A., et al. (2016). Distinct contribution of adult-born hippocampal granule cells to context encoding. Neuron 90 101–112. 10.1016/j.neuron.2016.02.019
    1. Darcet F., Gardier A. M., Gaillard R., David D. J., Guilloux J. P. (2016). Cognitive dysfunction in major depressive disorder. A translational review in animal models of the disease. Pharmaceuticals 9:E9. 10.3390/ph9010009
    1. de Carvalho S. C., Marcourakis T., Artes R., Gorenstein C. (2002). Memory performance in panic disorder patients after chronic use of clomipramine. J. Psychopharmacol. 16 220–226. 10.1177/026988110201600305
    1. du Jardin K. G., Jensen J. B., Sanchez C., Pehrson A. L. (2014). 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. Eur. Neuropsychopharmacol. 24 160–171. 10.1016/j.euroneuro.2013.07.001
    1. Fava M. (2003). Diagnosis and definition of treatment-resistant depression. Biol. Psychiatry 53 649–659. 10.1016/S0006-3223(03)00231-2
    1. Frampton J. E. (2016). Vortioxetine: a review in cognitive dysfunction in depression. Drugs 76 1675–1682. 10.1007/s40265-016-0655-3
    1. Gardier A. M., Guiard B. P., Guilloux J. P., Reperant C., Coudore F., David D. J. (2009). Interest of using genetically manipulated mice as models of depression to evaluate antidepressant drugs activity: a review. Fundam. Clin. Pharmacol. 23 23–42. 10.1111/j.1472-8206.2008.00640.x
    1. Gorenstein C., de Carvalho S. C., Artes R., Moreno R. A., Marcourakis T. (2006). Cognitive performance in depressed patients after chronic use of antidepressants. Psychopharmacology 185 84–92. 10.1007/s00213-005-0274-2
    1. Guilloux J. P., Mendez-David I., Pehrson A., Guiard B. P., Reperant C., Orvoen S., et al. (2013). Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Neuropharmacology 73 147–159. 10.1016/j.neuropharm.2013.05.014
    1. Guilloux J. P., Samuels B. A., Mendez-David I., Hu A., Levinstein M., Faye C., et al. (2017). S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice. Sci. Rep. 7:42946. 10.1038/srep42946
    1. Jensen J. B., du Jardin K. G., Song D., Budac D., Smagin G., Sanchez C., et al. (2014). Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation. Eur. Neuropsychopharmacol. 24 148–159. 10.1016/j.euroneuro.2013.10.011
    1. Katona C., Hansen T., Olsen C. K. (2012). A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int. Clin. Psychopharmacol. 27 215–223. 10.1097/YIC.0b013e3283542457
    1. Kheirbek M. A., Klemenhagen K. C., Sahay A., Hen R. (2012). Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat. Neurosci. 15 1613–1620. 10.1038/nn.3262
    1. Knegtering H., Eijck M., Huijsman A. (1994). Effects of antidepressants on cognitive functioning of elderly patients. A review. Drugs Aging 5 192–199. 10.2165/00002512-199405030-00005
    1. Lugert S., Kremer T., Jagasia R., Herrmann A., Aigner S., Giachino C., et al. (2017). Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis. Sci. Rep. 7:46543. 10.1038/srep46543
    1. Mahableshwarkar A. R., Zajecka J., Jacobson W., Chen Y., Keefe R. S. (2015). A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology 40 2025–2037. 10.1038/npp.2015.52
    1. Mahableshwarkar A. R., Zajecka J., Jacobson W., Chen Y., Keefe R. S. (2016). A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology 41:2961. 10.1038/npp.2016.181
    1. Marcourakis T., Gorenstein C., Gentil V. (1993). Clomipramine, a better reference drug for panic/agoraphobia. II. Psychomotor and cognitive effects. J. Psychopharmacol. 7 325–330. 10.1177/026988119300700403
    1. McIntyre R. S., Harrison J., Loft H., Jacobson W., Olsen C. K. (2016). The effects of vortioxetine on cognitive function in patients with major depressive disorder: a meta-analysis of three randomized controlled trials. Int. J. Neuropsychopharmacol. 10.1093/ijnp/pyw055 [Epub ahead of print].
    1. McIntyre R. S., Lophaven S., Olsen C. K. (2014). A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int. J. Neuropsychopharmacol. 17 1557–1567. 10.1017/S1461145714000546
    1. Mendez-David I., Guilloux J. P., Papp M., Tritschler L., Mocaer E., Gardier A. M., et al. (2017). S 47445 produces antidepressant- and anxiolytic-like effects through neurogenesis dependent and independent mechanisms. Front. Pharmacol. 8:462. 10.3389/fphar.2017.00462
    1. Mork A., Montezinho L. P., Miller S., Trippodi-Murphy C., Plath N., Li Y., et al. (2013). Vortioxetine (Lu AA21004), a novel multimodal antidepressant, enhances memory in rats. Pharmacol. Biochem. Behav. 105 41–50. 10.1016/j.pbb.2013.01.019
    1. Mork A., Pehrson A., Brennum L. T., Nielsen S. M., Zhong H., Lassen A. B., et al. (2012). Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J. Pharmacol. Exp. Ther. 340 666–675. 10.1124/jpet.111.189068
    1. O’Mahony C. M., Sweeney F. F., Daly E., Dinan T. G., Cryan J. F. (2010). Restraint stress-induced brain activation patterns in two strains of mice differing in their anxiety behaviour. Behav. Brain Res. 213 148–154. 10.1016/j.bbr.2010.04.038
    1. Paxinos G., Franklin K. B. J. (2001). The Mouse Brain in Stereotaxic Coordinates 2nd Edn. San Diego, CA: Academic Press.
    1. Popik P., Nikiforuk A. (2015). Attentional set-shifting paradigm in the rat. Curr. Protoc. Neurosci. 72 9.51.1–9.51.13. 10.1002/0471142301.ns0951s72
    1. Sahay A., Scobie K. N., Hill A. S., O’Carroll C. M., Kheirbek M. A., Burghardt N. S., et al. (2011a). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472 466–470. 10.1038/nature09817
    1. Sahay A., Wilson D. A., Hen R. (2011b). Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70 582–588. 10.1016/j.neuron.2011.05.012
    1. Sakalem M. E., Seidenbecher T., Zhang M., Saffari R., Kravchenko M., Wordemann S., et al. (2017). Environmental enrichment and physical exercise revert behavioral and electrophysiological impairments caused by reduced adult neurogenesis. Hippocampus 27 36–51. 10.1002/hipo.22669
    1. Sanchez C., Asin K. E., Artigas F. (2015). Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol. Ther. 145 43–57. 10.1016/j.pharmthera.2014.07.001
    1. Saxe M. D., Battaglia F., Wang J. W., Malleret G., David D. J., Monckton J. E., et al. (2006). Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl. Acad. Sci. U.S.A. 103 17501–17506. 10.1073/pnas.0607207103
    1. Saxe M. D., Malleret G., Vronskaya S., Mendez I., Garcia A. D., Sofroniew M. V., et al. (2007). Paradoxical influence of hippocampal neurogenesis on working memory. Proc. Natl. Acad. Sci. U.S.A. 104 4642–4646. 10.1073/pnas.0611718104
    1. Shelton D. J., Kirwan C. B. (2013). A possible negative influence of depression on the ability to overcome memory interference. Behav. Brain Res. 256 20–26. 10.1016/j.bbr.2013.08.016
    1. Smith J., Browning M., Conen S., Smallman R., Buchbjerg J., Larsen K. G., et al. (2017). Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls. Mol. Psychiatry 10.1038/mp.2017.104 [Epub ahead of print].
    1. Snyder J. S., Soumier A., Brewer M., Pickel J., Cameron H. A. (2011). Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476 458–461. 10.1038/nature10287
    1. Stein R. A., Strickland T. L. (1998). A review of the neuropsychological effects of commonly used prescription medications. Arch. Clin. Neuropsychol. 13 259–284. 10.1093/arclin/13.3.259
    1. Theunissen E. L., Street D., Hojer A. M., Vermeeren A., van Oers A., Ramaekers J. G. (2013). A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition. Clin. Pharmacol. Ther. 93 493–501. 10.1038/clpt.2013.39
    1. Treves A., Tashiro A., Witter M. P., Moser E. I. (2008). What is the mammalian dentate gyrus good for? Neuroscience 154 1155–1172. 10.1016/j.neuroscience.2008.04.073
    1. Tritschler L., Felice D., Colle R., Guilloux J. P., Corruble E., Gardier A. M., et al. (2014). Vortioxetine for the treatment of major depressive disorder. Expert Rev. Clin. Pharmacol. 7 731–745. 10.1586/17512433.2014.950655
    1. Trneckova L., Armario A., Hynie S., Sida P., Klenerova V. (2006). Differences in the brain expression of c-fos mRNA after restraint stress in Lewis compared to Sprague-Dawley rats. Brain Res. 1077 7–15. 10.1016/j.brainres.2006.01.029
    1. Tronel S., Belnoue L., Grosjean N., Revest J. M., Piazza P. V., Koehl M., et al. (2012). Adult-born neurons are necessary for extended contextual discrimination. Hippocampus 22 292–298. 10.1002/hipo.20895
    1. Wallace A., Pehrson A. L., Sanchez C., Morilak D. A. (2014). Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats. Int. J. Neuropsychopharmacol. 17 1695–1706. 10.1017/S1461145714000571
    1. Wang J. W., David D. J., Monckton J. E., Battaglia F., Hen R. (2008). Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J. Neurosci. 28 1374–1384. 10.1523/JNEUROSCI.3632-07.2008
    1. Westrich L., Haddjeri N., Dkhissi-Benyahya O., Sanchez C. (2015). Involvement of 5-HT(7) receptors in vortioxetine’s modulation of circadian rhythms and episodic memory in rodents. Neuropharmacology 89 382–390. 10.1016/j.neuropharm.2014.10.015
    1. Wu M. V., Hen R. (2014). Functional dissociation of adult-born neurons along the dorsoventral axis of the dentate gyrus. Hippocampus 24 751–761. 10.1002/hipo.22265
    1. Yassa M. A., Stark C. E. (2011). Pattern separation in the hippocampus. Trends Neurosci. 34 515–525. 10.1016/j.tins.2011.06.006

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