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Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

  • Alan L. Pehrson (a1) and Connie Sanchez (a1)


Monoamine-based treatments for depression have evolved greatly over the past several years, but shortcomings such as suboptimal efficacy, treatment lag, and residual cognitive dysfunction are still significant. Preclinical and clinical studies using compounds directly targeting glutamatergic neurotransmission present new opportunities for antidepressant treatment, with ketamine having a surprisingly rapid and sustained antidepressant effect that is presumably mediated through glutamate-dependent mechanisms. While direct modulation of glutamate transmission for antidepressant and cognition-enhancing actions may be hampered by nonspecific effects, indirect modulation through the serotonin (5-HT) system may be a viable alternative approach. Based on localization and function, 5-HT can modulate glutamate neurotransmission at least through the 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors, which presents a rational pharmacological opportunity for modulating glutamatergic transmission without the direct use of glutamatergic compounds. Combining one or more of these glutamate-modulating 5-HT targets with 5-HT transporter inhibition may offer new therapeutic opportunities. The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction.

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The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence . The written permission of Cambridge University Press must be obtained for commercial re-use.

Corresponding author

*Address for correspondence: Dr. Connie Sanchez, External Sourcing and Scientific Excellence, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652, USA. (Email


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The authors thank Dr. Huailing Zhong of U-Pharm Laboratories LLC (Parsippany, NJ) for insightful and very valuable help with writing the manuscript, and Dr. David Simpson for helpful insights and comments.



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1. Stahl, SM. Enhancing outcomes from major depression: using antidepressant combination therapies with multifunctional pharmacologic mechanisms from the initiation of treatment. CNS Spectr. 2010; 15(2): 7994.
2. Artigas, F, Adell, A, Celada, P. Pindolol augmentation of antidepressant response. Curr Drug Targets. 2006; 7(2): 139147.
3. Nelson, JC, Papakostas, GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009; 166(9): 980991.
4. Austin, MP, Mitchell, P, Goodwin, GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry. 2001; 178: 200206.
5. Lee, RS, Hermens, DF, Porter, MA, Redoblado-Hodge, MA. A meta-analysis of cognitive deficits in first-episode major depressive disorder. J Affect Disord. 2012; 140(2): 113124.
6. Mathews, A, MacLeod, C. Cognitive vulnerability to emotional disorders. Annu Rev Clin Psychol. 2005; 1: 167195.
7. Hasselbalch, BJ, Knorr, U, Kessing, LV. Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review. J Affect Disord. 2011; 134(1–3): 2031.
8. Naismith, SL, Longley, WA, Scott, EM, Hickie, IB. Disability in major depression related to self-rated and objectively-measured cognitive deficits: a preliminary study. BMC Psychiatry. 2007; 7: 3238.
9. Altamura, CA, Mauri, MC, Ferrara, A, etal. Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry. 1993; 150(11): 17311733.
10. Kim, JS, Schmid-Burgk, W, Claus, D, Kornhuber, HH. Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr. 1982; 232(4): 299304.
11. Maes, M, Verkerk, R, Vandoolaeghe, E, Lin, A, Scharpe, S. Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity. Acta Psychiatr Scand. 1998; 97(4): 302308.
12. Levine, J, Panchalingam, K, Rapoport, A, Gershon, S, McClure, RJ, Pettegrew, JW. Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry. 2000; 47(7): 586593.
13. Pangalos, MN, Malizia, AL, Francis, PT, etal. Effect of psychotropic drugs on excitatory amino acids in patients undergoing psychosurgery for depression. Br J Psychiatry. 1992; 160: 638642.
14. Francis, PT, Poynton, A, Lowe, SL, etal. Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem. Brain Res. 1989; 494(2): 315324.
15. Hashimoto, K, Sawa, A, Iyo, M. Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry. 2007; 62(11): 13101316.
16. Yuksel, C, Ongur, D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry. 2010; 68(9): 785794.
17. Beneyto, M, Meador-Woodruff, JH. Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology. 2008; 33(9): 21752186.
18. Beneyto, M, Kristiansen, LV, Oni-Orisan, A, McCullumsmith, RE, Meador-Woodruff, JH. Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology. 2007; 32(9): 18881902.
19. Bleakman, D, Alt, A, Witkin, JM. AMPA receptors in the therapeutic management of depression. CNS Neurol Disord Drug Targets. 2007; 6(2): 117126.
20. Mathew, SJ, Manji, HK, Charney, DS. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008; 33(9): 20802092.
21. Kendell, SF, Krystal, JH, Sanacora, G. GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin Ther Targets. 2005; 9(1): 153168.
22. Sanacora, G, Treccani, G, Popoli, M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012; 62(1): 6377.
23. Hashimoto, K. The role of glutamate on the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(7): 15581568.
24. Skolnick, P, Popik, P, Trullas, R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci. 2009; 30(11): 563569.
25. Schloss, P, Williams, DC. The serotonin transporter: a primary target for antidepressant drugs. J Psychopharmacol. 1998; 12(2): 115121.
26. Smythies, J. Section V. Serotonin system. Int Rev Neurobiol. 2005; 64: 217268.
27. Artigas, F. Serotonin receptors involved in antidepressant effects. Pharmacol Ther. 2013; 137(1): 119131.
28. Gigliucci, V, O'Dowd, G, Casey, S, etal. Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. Psychopharmacology (Berl). 2013; 228(1): 157166.
29. Nutt, DJ. Beyond psychoanaleptics—can we improve antidepressant drug nomenclature? J Psychopharmacol. 2009; 23(4): 343345.
30. Stahl, SM, Lee-Zimmerman, C, Cartwright, S, Morrissette, DA. Serotonergic drugs for depression and beyond. Curr Drug Targets. 2013; 14(5): 578585.
31. Javitt, DC, Schoepp, D, Kalivas, PW, etal. Translating glutamate: from pathophysiology to treatment. Sci Transl Med. 2011; 3(102): 102mr2.
32. Li, N, Lee, B, Liu, RJ, etal. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010; 329(5994): 959964.
33. Catena-Dell'Osso, M, Fagiolini, A, Rotella, F, Baroni, S, Marazziti, D. Glutamate system as target for development of novel antidepressants. CNS Spectr. In press.
34. McCarthy, DJ, Alexander, R, Smith, MA, etal. Glutamate-based depression GBD. Med Hypotheses. 2012; 78(5): 675681.
35. Zarate, CA Jr, Singh, JB, Carlson, PJ, etal. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63(8): 856864.
36. Preskorn, SH, Baker, B, Kolluri, S, etal. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol. 2008; 28(6): 631637.
37. Zarate, CA Jr, Singh, JB, Quiroz, JA, etal. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006; 163(1): 153155.
38. Anticevic, A, Gancsos, M, Murray, JD, etal. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci U S A. 2012; 109(41): 1672016725.
39. Maeng, S, Zarate, CA Jr, Du, J, etal. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008; 63(4): 349352.
40. Tripp, A, Oh, H, Guilloux, JP, Martinowich, K, Lewis, DA, Sibille, E. Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. Am J Psychiatry. 2012; 169(11): 11941202.
41. Murphy, SE, Norbury, R, O'Sullivan, U, Cowen, PJ, Harmer, CJ. Effect of a single dose of citalopram on amygdala response to emotional faces. Br J Psychiatry. 2009; 194(6): 535540.
42. Norbury, R, Mackay, CE, Cowen, PJ, Goodwin, GM, Harmer, CJ. The effects of reboxetine on emotional processing in healthy volunteers: an fMRI study. Mol Psychiatry. 2008; 13(11): 10111020.
43. Knapp, RJ, Goldenberg, R, Shuck, C, etal. Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur J Pharmacol. 2002; 440(1): 2735.
44. O'Neill, MJ, Bleakman, D, Zimmerman, DM, Nisenbaum, ES. AMPA receptor potentiators for the treatment of CNS disorders. Curr Drug Targets CNS Neurol Disord. 2004; 3(3): 181194.
45. Hahn, CG, Gyulai, L, Baldassano, CF, Lenox, RH. The current understanding of lamotrigine as a mood stabilizer. J Clin Psychiatry. 2004; 65(6): 791804.
46. Obrocea, GV, Dunn, RM, Frye, MA, etal. Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Biol Psychiatry. 2002; 51(3): 253260.
47. Normann, C, Hummel, B, Scharer, LO, etal. Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study. J Clin Psychiatry. 2002; 63(4): 337344.
48. Zarate, CA Jr, Payne, JL, Quiroz, J, etal. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004; 161(1): 171174.
49. Sanacora, G, Kendell, SF, Fenton, L, Coric, V, Krystal, JH. Riluzole augmentation for treatment-resistant depression. Am J Psychiatry. 2004; 161(11): 2132.
50. Belozertseva, IV, Kos, T, Popik, P, Danysz, W, Bespalov, AY. Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests. Eur Neuropsychopharmacol. 2007; 17(3): 172179.
51. Chaki, S, Yoshikawa, R, Hirota, S, etal. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology. 2004; 46(4): 457467.
52. Higgins, GA, Ballard, TM, Kew, JN, etal. Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology. 2004; 46(7): 907917.
53. Riedel, G, Platt, B, Micheau, J. Glutamate receptor function in learning and memory. Behav Brain Res. 2003; 140(1–2): 147.
54. Teixeira, CM, Pomedli, SR, Maei, HR, Kee, N, Frankland, PW. Involvement of the anterior cingulate cortex in the expression of remote spatial memory. J Neurosci. 2006; 19(29): 75557564.
55. Homayoun, H, Stefani, MR, Adams, BW, Tamagan, GD, Moghaddam, B. Functional interaction between NMDA and mGlu5 receptors: effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology. 2004; 29(7): 12591269.
56. Moghaddam, B. Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl). 2004; 174(1): 3944.
57. Hamlyn, E, Brand, L, Shahid, M, Harvey, BH. The ampakine, Org 26576, bolsters early spatial reference learning and retrieval in the Morris water maze: a subchronic, dose-ranging study in rats. Behav Pharmacol. 2009; 20(7): 662667.
58. Fowler, SW, Walker, JM, Klakotskaia, D, etal. Effects of a metabotropic glutamate receptor 5 positive allosteric modulator, CDPPB, on spatial learning task performance in rodents. Neurobiol Learn Mem. 2013; 99: 2531.
59. Ozawa, T, Kumeji, M, Yamada, K, Ichitani, Y. D-Cycloserine enhances spatial memory in spontaneous place recognition in rats. Neurosci Lett. 2012; 509(1): 1316.
60. Choi, DW, Maulucci-Gedde, M, Kriegstein, AR. Glutamate neurotoxicity in cortical cell culture. J Neurosci. 1987; 7(2): 357368.
61. Zajaczkowski, W, Frankiewicz, T, Parsons, CG, Danysz, W. Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP. Neuropharmacology. 1997; 36(7): 961971.
62. Sprouse, JS, Aghajanian, GK. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse. 1987; 1(1): 39.
63. Blier, P, de Montigny, C. Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology. 1999; 21(2 suppl): 91S98S.
64. El Mansari, M, Sanchez, C, Chouvet, G, Renaud, B, Haddjeri, N. Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain. Neuropsychopharmacology. 2005; 30(7): 12691277.
65. Kennett, GA, Dourish, CT, Curzon, G. Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression. Eur J Pharmacol. 1987; 134(3): 265274.
66. Robinson, DS, Rickels, K, Feighner, J, etal. Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. J Clin Psychopharmacol. 1990; 10(3 suppl): 67S76S.
67. Martinez, D, Hwang, D, Mawlawi, O, etal. Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology. 2001; 24(3): 209229.
68. Santana, N, Bortolozzi, A, Serrats, J, Mengod, G, Artigas, F. Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex. 2004; 14(10): 11001109.
69. Aznar, S, Qian, Z, Shah, R, Rahbek, B, Knudsen, GM. The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain. Brain Res. 2003; 959(1): 5867.
70. Luscher, C, Jan, LY, Stoffel, M, Malenka, RC, Nicoll, RA. G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron. 1997; 19(3): 687695.
71. Llado-Pelfort, L, Santana, N, Ghisi, V, Artigas, F, Celada, P. 5-HT1A receptor agonists enhance pyramidal cell firing in prefrontal cortex through a preferential action on GABA interneurons. Cereb Cortex. 2012; 22(7): 14871497.
72. Llado-Pelfort, L, Assie, MB, Newman-Tancredi, A, Artigas, F, Celada, P. Preferential in vivo action of F15599, a novel 5-HT(1A) receptor agonist, at postsynaptic 5-HT(1A) receptors. Br J Pharmacol. 2010; 160(8): 19291940.
73. Wang, S, Zhang, QJ, Liu, J, etal. The firing activity of pyramidal neurons in medial prefrontal cortex and their response to 5-hydroxytryptamine-1A receptor stimulation in a rat model of Parkinson's disease. Neuroscience. 2009; 162(4): 10911100.
74. Levkovitz, Y, Segal, M. Serotonin 5-HT1A receptors modulate hippocampal reactivity to afferent stimulation. J Neurosci. 1997; 17(14): 55915598.
75. Newman-Tancredi, A, Martel, JC, Assie, MB, etal. Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist. Br J Pharmacol. 2009; 156(2): 338353.
76. Depoortere, R, Auclair, AL, Bardin, L, etal. F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists. Eur Neuropsychopharmacol. 2010; 20(9): 641654.
77. Meneses, A, Hong, E. 5-HT1A receptors modulate the consolidation of learning in normal and cognitively impaired rats. Neurobiol Learn Mem. 1999; 71(2): 207218.
78. Herremans, AH, Hijzen, TH, Olivier, B, Slangen, JL. Serotonergic drug effects on a delayed conditional discrimination task in the rat; involvement of the 5-HT1A receptor in working memory. J Psychopharmacol. 1995; 9(3): 242250.
79. Tsuji, M, Takeda, H, Matsumiya, T. Modulation of passive avoidance in mice by the 5-HT1A receptor agonist flesinoxan: comparison with the benzodiazepine receptor agonist diazepam. Neuropsychopharmacology. 2003; 28(4): 664674.
80. Horiguchi, M, Meltzer, HY. The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats. Psychopharmacology (Berl). 2012; 221(2): 205215.
81. Sari, Y. Serotonin1B receptors: from protein to physiological function and behavior. Neurosci Biobehav Rev. 2004; 28(6): 565582.
82. Peddie, CJ, Davies, HA, Colyer, FM, Stewart, MG, Rodriguez, JJ. A subpopulation of serotonin 1B receptors colocalize with the AMPA receptor subunit GluR2 in the hippocampal dentate gyrus. Neurosci Lett. 2010; 485(3): 251255.
83. Peddie, CJ, Davies, HA, Colyer, FM, Stewart, MG, Rodriguez, JJ. Dendritic colocalisation of serotonin1B receptors and the glutamate NMDA receptor subunit NR1 within the hippocampal dentate gyrus: an ultrastructural study. J Chem Neuroanat. 2008; 36(1): 1726.
84. Cai, X, Kallarackal, AJ, Kvarta, MD, etal. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci. 2013; 16(4): 464472.
85. Ait, AD, Segu, L, Naili, S, Buhot, MC. Serotonin 1B receptor regulation after dorsal subiculum deafferentation. Brain Res Bull. 1995; 38(1): 1723.
86. Boeijinga, PH, Boddeke, HW. Activation of 5-HT1B receptors suppresses low but not high frequency synaptic transmission in the rat subicular cortex in vitro. Brain Res. 1996; 721(1–2): 5965.
87. Mlinar, B, Falsini, C, Corradetti, R. Pharmacological characterization of 5-HT(1B) receptor-mediated inhibition of local excitatory synaptic transmission in the CA1 region of rat hippocampus. Br J Pharmacol. 2003; 138(1): 7180.
88. Stepien, A, Chalimoniuk, M, Strosznajder, J. Serotonin 5HT1B/1D receptor agonists abolish NMDA receptor-evoked enhancement of nitric oxide synthase activity and cGMP concentration in brain cortex slices. Cephalalgia. 1999; 19(10): 859865.
89. Svenningsson, P, Chergui, K, Rachleff, I, etal. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006; 311(5757): 7780.
90. Tatarczynska, E, Klodzinska, A, Stachowicz, K, Chojnacka-Wojcik, E. Effects of a selective 5-HT1B receptor agonist and antagonists in animal models of anxiety and depression. Behav Pharmacol. 2004; 15(8): 523534.
91. Skelin, I, Kovacevic, T, Sato, H, Diksic, M. The opposite effect of a 5-HT1B receptor agonist on 5-HT synthesis, as well as its resistant counterpart, in an animal model of depression. Brain Res Bull. 2012; 88(5): 477486.
92. Redrobe, JP, MacSweeney, CP, Bourin, M. The role of 5-HT1A and 5-HT1B receptors in antidepressant drug actions in the mouse forced swimming test. Eur J Pharmacol. 1996; 318(2–3): 213220.
93. Buhot, MC, Patra, SK, Naili, S. Spatial memory deficits following stimulation of hippocampal 5-HT1B receptors in the rat. Eur J Pharmacol. 1995; 285(3): 221228.
94. Meneses, A. Could the 5-HT1B receptor inverse agonism affect learning consolidation? Neurosci Biobehav Rev. 2001; 25(2): 193201.
95. Eriksson, TM, Madjid, N, Elvander-Tottie, E, etal. Blockade of 5-HT 1B receptors facilitates contextual aversive learning in mice by disinhibition of cholinergic and glutamatergic neurotransmission. Neuropharmacology. 2008; 54(7): 10411050.
96. Thompson, AJ, Lummis, SC. 5-HT3 receptors. Curr Pharm Des. 2006; 12(28): 36153630.
97. Puig, MV, Santana, N, Celada, P, Mengod, G, Artigas, F. In vivo excitation of GABA interneurons in the medial prefrontal cortex through 5-HT3 receptors. Cereb Cortex. 2004; 14(12): 13651375.
98. Morales, M, Bloom, FE. The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon. J Neurosci. 1997; 17(9): 31573167.
99. Reznic, J, Staubli, U. Effects of 5-HT3 receptor antagonism on hippocampal cellular activity in the freely moving rat. J Neurophysiol. 1997; 77(1): 517521.
100. Ashby, CR Jr, Minabe, Y, Edwards, E, Wang, RY. 5-HT3-like receptors in the rat medial prefrontal cortex: an electrophysiological study. Brain Res. 1991; 550(2): 181191.
101. Liang, X, Arvanov, VL, Wang, RY. Inhibition of NMDA-receptor mediated response in the rat medial prefrontal cortical pyramidal cells by the 5-HT3 receptor agonist SR 57227A and 5-HT: intracellular studies. Synapse. 1998; 29(3): 257268.
102. Staubli, U, Xu, FB. Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat. J Neurosci. 1995; 15(3 pt 2): 24452452.
103. Sanchez, C, Robichaud, PJ, Pehrson, A, Leiser, SC. The effects of the multimodal antidepressant Lu AA21004 on attention and vigilance measured as EEG activity in the rat. Eur Neuropsychopharmacol. 2012; 22(suppl 2): S243S244.
104. Pitsikas, N, Borsini, F. Itasetron (DAU 6215) prevents age-related memory deficits in the rat in a multiple choice avoidance task. Eur J Pharmacol. 1996; 311(2–3): 115119.
105. Roychoudhury, M, Kulkarni, SK. Effects of ondansetron on short-term memory retrieval in mice. Methods Find Exp Clin Pharmacol. 1997; 19(1): 4346.
106. Pehrson, A, Gaarn du Jardin Nielsen, K, Jensen, JB, Sanchez, C. The novel multimodal antidepressant Lu AA21004 improves memory performance in 5-HT depleted rats via 5-HT3 and 5-HT1A receptor mechanisms. Eur Neuropsychopharmacol. 2012; 22(suppl 2): S269S269.
107. Fontana, DJ, Daniels, SE, Henderson, C, Eglen, RM, Wong, EH. Ondansetron improves cognitive performance in the Morris water maze spatial navigation task. Psychopharmacology (Berl). 1995; 120(4): 409417.
108. Carey, GJ, Costall, B, Domeney, AM, etal. Ondansetron and arecoline prevent scopolamine-induced cognitive deficits in the marmoset. Pharmacol Biochem Behav. 1992; 42(1): 7583.
109. Martin, P, Gozlan, H, Puech, AJ. 5-HT3 receptor antagonists reverse helpless behaviour in rats. Eur J Pharmacol. 1992; 212(1): 7378.
110. Mahesh, R, Bhatt, S, Devadoss, T, etal. Antidepressant potential of 5-HT3 receptor antagonist, N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n). J Young Pharm. 2012; 4(4): 235244.
111. Kos, T, Popik, P, Pietraszek, M, etal. Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice. Eur Neuropsychopharmacol. 2006; 16(4): 297310.
112. Mørk, A, Pehrson, A, Tottrup, BLT, etal. Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J Pharmacol Exp Ther. 2012; 340(3): 666675.
113. Hedlund, PB, Sutcliffe, JG. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol Sci. 2004; 25(9): 481486.
114. Harsing, LG Jr. The pharmacology of the neurochemical transmission in the midbrain raphe nuclei of the rat. Curr Neuropharmacol. 2006; 4(4): 313339.
115. Duncan, MJ, Congleton, MR. Neural mechanisms mediating circadian phase resetting by activation of 5-HT(7) receptors in the dorsal raphe: roles of GABAergic and glutamatergic neurotransmission. Brain Res. 2010; 1366: 110119.
116. Bickmeyer, U, Heine, M, Manzke, T, Richter, DW. Differential modulation of I(h) by 5-HT receptors in mouse CA1 hippocampal neurons. Eur J Neurosci. 2002; 16(2): 209218.
117. Fan, LL, Zhang, QJ, Liu, J, etal. In vivo effect of 5-HT(7) receptor agonist on pyramidal neurons in medial frontal cortex of normal and 6-hydroxydopamine-lesioned rats: an electrophysiological study. Neuroscience. 2011; 190: 328338.
118. Tokarski, K, Zahorodna, A, Bobula, B, Hess, G. 5-HT7 receptors increase the excitability of rat hippocampal CA1 pyramidal neurons. Brain Res. 2003; 993(1–2): 230234.
119. Tokarski, K, Kusek, M, Hess, G. 5-HT7 receptors modulate GABAergic transmission in rat hippocampal CA1 area. J Physiol Pharmacol. 2011; 62(5): 535540.
120. Bonaventure, P, Kelly, L, Aluisio, L, etal. Selective blockade of 5-hydroxytryptamine (5-HT)7 receptors enhances 5-HT transmission, antidepressant-like behavior, and rapid eye movement sleep suppression induced by citalopram in rodents. J Pharmacol Exp Ther. 2007; 321(2): 690698.
121. Hedlund, PB. The 5-HT7 receptor and disorders of the nervous system: an overview. Psychopharmacology (Berl). 2009; 206(3): 345354.
122. Stahl, SM. The serotonin-7 receptor as a novel therapeutic target. J Clin Psychiatry. 2010; 71(11): 14141415.
123. Meneses, A. Effects of the 5-HT7 receptor antagonists SB-269970 and DR 4004 in autoshaping Pavlovian/instrumental learning task. Behav Brain Res. 2004; 155(2): 275282.
124. McLean, SL, Woolley, ML, Thomas, D, Neill, JC. Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat. Psychopharmacology (Berl). 2009; 206(3): 403414.
125. Horiguchi, M, Huang, M, Meltzer, HY. The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats. J Pharmacol Exp Ther. 2011; 338(2): 605614.
126. Waters, KA, Stean, TO, Hammond, B, etal. Effects of the selective 5-HT(7) receptor antagonist SB-269970 in animal models of psychosis and cognition. Behav Brain Res. 2012; 228(1): 211218.
127. Bonaventure, P, Aluisio, L, Shoblock, J, etal. Pharmacological blockade of serotonin 5-HT(7) receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission. PLoS One. 2011; 6(6): e20210.
128. Nikiforuk, A. Selective blockade of 5-HT7 receptors facilitates attentional set-shifting in stressed and control rats. Behav Brain Res. 2012; 226(1): 118123.
129. Heinrich, T, Bottcher, H, Gericke, R, etal. Synthesis and structure–activity relationship in a class of indolebutylpiperazines as dual 5-HT(1A) receptor agonists and serotonin reuptake inhibitors. J Med Chem. 2004; 47(19): 46844692.
130. Page, ME, Cryan, JF, Sullivan, A, etal. Behavioral and neurochemical effects of 5-(4-[4-(5-cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist. J Pharmacol Exp Ther. 2002; 302(3): 12201227.
131. De Paulis, T. Drug evaluation: vilazodone—a combined SSRI and 5-HT1A partial agonist for the treatment of depression. IDrugs. 2007; 10(3): 193201.
132. Guay, DR. Vilazodone hydrochloride, a combined SSRI and 5-HT1A receptor agonist for major depressive disorder. Consult Pharm. 2012; 27(12): 857867.
133. Wang, SM, Han, C, Lee, SJ, Patkar, AA, Pae, CU. A review of current evidence for vilazodone in major depressive disorder. Int J Psychiatry Clin Pract. In press.
134. Bang-Andersen, B, Ruhland, T, Jørgensen, M, etal. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011; 54(9): 32063221.
135. Westrich, L, Pehrson, A, Zhong, H, etal. In vitro and in vivo effects of the multimodal antidepressant vortioxetine (Lu AA21004) at human and rat targets. Int J Psychiatry Clin Pract. 2012; 5(suppl 1): 4747.
136. Pehrson, AL, Cremers, T, Betry, C, etal. Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters—a rat microdialysis and electrophysiology study. Eur Neuropsychopharmacol. 2013; 23(2): 133145.
137. Bétry, C, Pehrson, AL, Etievant, A, etal. The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT3 receptor antagonism. Int J Neuropsychopharmacol. 2013; 16(5): 11151127.
138. Li, Y, Pehrson, AL, Budac, DP, Sanchez, C, Gulinello, M. A rodent model of premenstrual dysphoria: progesterone withdrawal induces depression-like behavior that is differentially sensitive to classes of antidepressants. Behav Brain Res. 2012; 234(2): 238247.
139. Alvarez, E, Perez, V, Dragheim, M, Loft, H, Artigas, F. A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012; 15(5): 589600.
140. Katona, C, Hansen, T, Olsen, CK. 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. 2012; 27(4): 215223.
141. Baldwin, DS, Loft, H, Dragheim, M. A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD). Eur Neuropsychopharmacol. 2012; 22(7): 482491.
142. Baldwin, DS, Loft, H, Florea, I. Lu AA21004, a multimodal psychotropic agent, in the prevention of relapse in adult patients with generalized anxiety disorder. Int Clin Psychopharmacol. 2012; 27(4): 197207.
143. Boulenger, JP, Loft, H, Florea, I. A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder. J Psychopharmacol. 2012; 26(11): 14081416.
144. Henigsberg, N, Mahableshwarkar, AR, Jacobsen, P, Chen, Y, Thase, ME. A randomized, double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple doses of Lu AA21004 in adults with major depressive disorder. J Clin Psychiatry. 2012; 73(7): 953959.
145. Baldwin, DS, Hansen, T, Florea, I. Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder. Curr Med Res Opin. 2012; 28(10): 17171724.
146. Mahableshwarkar, AR, Jacobsen, PL, Chen, Y. A randomized, double-blind trial of 2.5 mg and 5 mg vortioxetine (Lu AA21004) versus placebo for 8 weeks in adults with major depressive disorder. Curr Med Res Opin. 2013; 29(3): 217226.
147. Jain, R, Mahableshwarkar, AR, Jacobsen, PL, Chen, Y, Thase, ME. A randomized, double-blind, placebo-controlled 6-wk trial of the efficacy and tolerability of 5 mg vortioxetine in adults with major depressive disorder. Int J Neuropsychopharmacol. 2013; 16(2): 313321.
148. Mørk, A, Montezinho, LP, Miller, S, etal. Vortioxetine (Lu AA21004), a novel multimodal antidepressant, enhances memory in rats. Pharmacol Biochem Behav. 2013; 105C: 4150.
149. Berman, RM, Cappiello, A, Anand, A, etal. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000; 47(4): 351354.
150. Koliaki, CC, Messini, C, Tsolaki, M. Clinical efficacy of aniracetam, either as monotherapy or combined with cholinesterase inhibitors, in patients with cognitive impairment: a comparative open study. CNS Neurosci Ther. 2012; 18(4): 302312.
151. Li, X, Tizzano, JP, Griffey, K, etal. Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology. 2001; 40(8): 10281033.
152. Bespalov, AY, van Gaalen, MM, Sukhotina, IA, etal. Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression. Eur J Pharmacol. 2008; 592(1–3): 96102.
153. Burgdorf, J, Zhang, XL, Nicholson, KL, etal. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013; 38(5): 729742.


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