Translating the promise of 5HT4 receptor agonists for the treatment of depression

Susannah E Murphy, Angharad N de Cates, Amy L Gillespie, Beata R Godlewska, Jessica C Scaife, Lucy C Wright, Philip J Cowen, Catherine J Harmer, Susannah E Murphy, Angharad N de Cates, Amy L Gillespie, Beata R Godlewska, Jessica C Scaife, Lucy C Wright, Philip J Cowen, Catherine J Harmer

Abstract

Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.

Trial registration: ClinicalTrials.gov NCT03516604 NCT03515733.

Keywords: Antidepressants; cognition; emotion; serotonin.

References

    1. Abboussi, O., Said, N., Fifel, K., Lakehayli, S., Tazi, A., & El Ganouni, S. (2016). Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence. Metabolic Brain Disease, 31(2), 321–327. doi:10.1007/s11011-015-9753-2.
    1. Amigo, J., Diaz, A., Pilar-Cuellar, F., Vidal, R., Martin, A., Compan, V., … Castro, E. (2016). The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: Adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor. Neuropharmacology, 111, 47–58. doi:10.1016/j.neuropharm.2016.08.037.
    1. Artigas, F. (2013). Serotonin receptors involved in antidepressant effects. Pharmacology and Therapeutics, 137(1), 119–131. doi:10.1016/j.pharmthera.2012.09.006.
    1. Bai, M., Zhu, X. Z., Zhang, Y., Zhang, S., Zhang, L., Xue, L., … Zhang, X. (2014). Anhedonia was associated with the dysregulation of hippocampal HTR4 and microRNA Let-7a in rats. Physiology and Behavior, 129, 135–141. doi:10.1016/j.physbeh.2014.02.035.
    1. Barthet, G., Framery, B., Gaven, F., Pellissier, L., Reiter, E., Claeysen, S., … Dumuis, A. (2007). 5-hydroxytryptamine 4 receptor activation of the extracellular signal-regulated kinase pathway depends on Src activation but not on G protein or beta-arrestin signaling. Molecular Biology of the Cell, 18(6), 1979–1991. doi:10.1091/mbc.e06-12-1080.
    1. Beliveau, V., Ganz, M., Feng, L., Ozenne, B., Hojgaard, L., Fisher, P. M., … Knudsen, G. M. (2017). A high-resolution in vivo atlas of the human brain's serotonin system. Journal of Neuroscience, 37(1), 120–128. doi:10.1523/jneurosci.2830-16.2016.
    1. Bell, R., Duke, A. A., Gilmore, P. E., Page, D., & Begue, L. (2014). Anxiolytic-like effects observed in rats exposed to the elevated zero-maze following treatment with 5-HT2/5-HT3/5-HT4 ligands. Scientific Reports, 4, 3881. doi:10.1038/srep03881.
    1. Bijak, M., & Misgeld, U. (1997). Effects of serotonin through serotonin1A and serotonin4 receptors on inhibition in the Guinea-pig dentate gyrus in vitro. Neuroscience, 78(4), 1017–1026. doi:10.1016/s0306-4522(96)00666-5.
    1. Blier, P., Piñeyro, G., el Mansari, M., Bergeron, R., & de Montigny, C. (1998). Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission. Annals of the New York Academy of Sciences, 861, 204–216.
    1. Bockaert, J., Claeysen, S., Compan, V., & Dumuis, A. (2004). 5-HT4 receptors. Current Drug Targets: CNS and Neurological Disorders, 3(1), 39–51.
    1. Bockaert, J., Claeysen, S., Compan, V., & Dumuis, A. (2008). 5-HT(4) receptors: History, molecular pharmacology and brain functions. Neuropharmacology, 55(6), 922–931. doi:10.1016/j.neuropharm.2008.05.013.
    1. Bonaventure, P., Hall, H., Gommeren, W., Cras, P., Langlois, X., Jurzak, M., & Leysen, J. E. (2000). Mapping of serotonin 5-HT(4) receptor mRNA and ligand binding sites in the post-mortem human brain. Synapse (New York, N.Y.), 36(1), 35–46. doi:10.1002/(sici)1098-2396(200004)36:1<35::aid-syn4>;2-y.
    1. Bonhomme, N., De Deurwaerdere, P., Le Moal, M., & Spampinato, U. (1995). Evidence for 5-HT4 receptor subtype involvement in the enhancement of striatal dopamine release induced by serotonin: A microdialysis study in the halothane-anesthetized rat. Neuropharmacology, 34(3), 269–279. doi:10.1016/0028-3908(94)00145-i.
    1. Burghardt, N. S., Bush, D. E., McEwen, B. S., & LeDoux, J. E. (2007). Acute selective serotonin reuptake inhibitors increase conditioned fear expression: Blockade with a 5-HT(2C) receptor antagonist. Biological Psychiatry, 62(10), 1111–1118. doi:10.1016/j.biopsych.2006.11.023.
    1. Cachard-Chastel, M., Devers, S., Sicsic, S., Langlois, M., Lezoualc'h, F., Gardier, A. M., & Belzung, C. (2008). Prucalopride and donepezil act synergistically to reverse scopolamine-induced memory deficit in C57Bl/6j mice. Behavioural Brain Research, 187(2), 455–461. doi:10.1016/j.bbr.2007.10.008.
    1. Cachard-Chastel, M., Lezoualc'h, F., Dewachter, I., Deloménie, C., Croes, S., Devijver, H., … Gardier, A. M. (2007). 5-HT4 receptor agonists increase sAPPalpha levels in the cortex and hippocampus of male C57BL/6j mice. British Journal of Pharmacology, 150(7), 883–892. doi:10.1038/sj.bjp.0707178.
    1. Cai, X., Flores-Hernandez, J., Feng, J., & Yan, Z. (2002). Activity-dependent bidirectional regulation of GABA(A) receptor channels by the 5-HT(4) receptor-mediated signalling in rat prefrontal cortical pyramidal neurons. Journal of Physiology, 540(Pt 3), 743–759.
    1. Castello, J., LeFrancois, B., Flajolet, M., Greengard, P., Friedman, E., & Rebholz, H. (2018). CK2 regulates 5-HT4 receptor signaling and modulates depressive-like behavior. Molecular Psychiatry, 23(4), 872–882. doi:10.1038/mp.2017.240.
    1. Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., … Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet (London, England), 391(10128), 1357–1366. doi:10.1016/S0140-6736(17)32802-7.
    1. Compan, V., Daszuta, A., Salin, P., Sebben, M., Bockaert, J., & Dumuis, A. (1996). Lesion study of the distribution of serotonin 5-HT4 receptors in rat basal ganglia and hippocampus. European Journal of Neuroscience, 8(12), 2591–2598.
    1. Conductier, G., Dusticier, N., Lucas, G., Cote, F., Debonnel, G., Daszuta, A., … Compan, V. (2006). Adaptive changes in serotonin neurons of the raphe nuclei in 5-HT(4) receptor knock-out mouse. European Journal of Neuroscience, 24(4), 1053–1062. doi:10.1111/j.1460-9568.2006.04943.x.
    1. Consolo, S., Arnaboldi, S., Giorgi, S., Russi, G., & Ladinsky, H. (1994). 5-HT4 Receptor stimulation facilitates acetylcholine release in rat frontal cortex. Neuroreport, 5(10), 1230–1232.
    1. Costall, B., & Naylor, R. J. (1997). The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test. British Journal of Pharmacology, 122(6), 1105–1118. doi:10.1038/sj.bjp.0701513.
    1. Craig, D. A., & Clarke, D. E. (1990). Pharmacological characterization of a neuronal receptor for 5-hydroxytryptamine in Guinea pig ileum with properties similar to the 5-hydroxytryptamine receptor. Journal of Pharmacology and Experimental Therapeutics, 252(3), 1378–1386.
    1. Cryan, J. F., & Lucki, I. (2000). 5-HT4 receptors do not mediate the antidepressant-like behavioral effects of fluoxetine in a modified forced swim test. European Journal of Pharmacology, 409(3), 295–299. doi:10.1016/s0014-2999(00)00858-x.
    1. Darcet, F., Gardier, A. M., David, D. J., & Guilloux, J. P. (2016). Chronic 5-HT4 receptor agonist treatment restores learning and memory deficits in a neuroendocrine mouse model of anxiety/depression. Neuroscience Letters, 616, 197–203. doi:10.1016/j.neulet.2016.01.055.
    1. De Maeyer, J. H., Lefebvre, R. A., & Schuurkes, J. A. (2008). 5-HT4 Receptor agonists: Similar but not the same. Neurogastroenterology and Motility, 20(2), 99–112. doi:10.1111/j.1365-2982.2007.01059.x.
    1. Dumuis, A., Bouhelal, R., Sebben, M., Cory, R., & Bockaert, J. (1988). A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Molecular Pharmacology, 34(6), 880–887.
    1. Eriksson, T. M., Delagrange, P., Spedding, M., Popoli, M., Mathe, A. A., Ogren, S. O., & Svenningsson, P. (2012). Emotional memory impairments in a genetic rat model of depression: Involvement of 5-HT/MEK/Arc signaling in restoration. Molecular Psychiatry, 17(2), 173–184. doi:10.1038/mp.2010.131.
    1. Faye, C., Hen, R., Guiard, B., Denny, C., Gardier, A., Mendez-David, I., & David, D. (2019). Rapid anxiolytic effects of RS67333, a serotonin type 4 receptor agonist, and diazepam, a benzodiazepine, are mediated by projections from the prefrontal cortex to the dorsal raphe nucleus. Biological Psychiatry 87(6):514-525. doi:10.1016/j.biopsych.2019.08.009.
    1. Fontana, D. J., Daniels, S. E., Wong, E. H., Clark, R. D., & Eglen, R. M. (1997). The effects of novel, selective 5-hydroxytryptamine (5-HT)4 receptor ligands in rat spatial navigation. Neuropharmacology, 36(4-5), 689–696.
    1. Frazer, A., & Benmansour, S. (2002). Delayed pharmacological effects of antidepressants. Molecular Psychiatry, 7 (Suppl 1), S23–S28. doi:10.1038/sj.mp.4001015.
    1. Galeotti, N., Ghelardini, C., & Bartolini, A. (1998). Role of 5-HT4 receptors in the mouse passive avoidance test. Journal of Pharmacology and Experimental Therapeutics, 286(3), 1115–1121.
    1. Ge, J., & Barnes, N. M. (1996). 5-HT4 receptor-mediated modulation of 5-HT release in the rat hippocampus in vivo. British Journal of Pharmacology, 117(7), 1475–1480. doi:10.1111/j.1476-5381.1996.tb15309.x.
    1. Godlewska, B. R., & Harmer, C. J. (2020). Cognitive neuropsychological theory of antidepressant action: A modern-day approach to depression and its treatment. Psychopharmacology. doi:10.1007/s00213-019-05448-0.
    1. Goethe, J. W., Woolley, S. B., Cardoni, A. A., Woznicki, B. A., & Piez, D. A. (2007). Selective serotonin reuptake inhibitor discontinuation: Side effects and other factors that influence medication adherence. Journal of Clinical Psychopharmacology, 27(5), 451–458. doi:10.1097/jcp.0b013e31815152a5.
    1. Gomez-Lazaro, E., Garmendia, L., Beitia, G., Perez-Tejada, J., Azpiroz, A., & Arregi, A. (2012). Effects of a putative antidepressant with a rapid onset of action in defeated mice with different coping strategies. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 38(2), 317–327. doi:10.1016/j.pnpbp.2012.04.019.
    1. Goodwin, G. M., Price, J., De Bodinat, C., & Laredo, J. (2017). Emotional blunting with antidepressant treatments: A survey among depressed patients. Journal of Affective Disorders, 221, 31–35. doi:10.1016/j.jad.2017.05.048.
    1. Haahr, M. E., Fisher, P., Holst, K., Madsen, K., Jensen, C. G., Marner, L., & Hasselbalch, S. (2013). The 5-HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans. Human Brain Mapping, 34(11), 3066–3074. doi:10.1002/hbm.22123.
    1. Haahr, M. E., Fisher, P. M., Jensen, C. G., Frokjaer, V. G., Mahon, B. M., Madsen, K., & Knudsen, G. M. (2014). Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: A [11C]SB207145 PET study. Molecular Psychiatry, 19(4), 427–432. doi:10.1038/mp.2013.147.
    1. Hagena, H., & Manahan-Vaughan, D. (2017). The serotonergic 5-HT4 receptor: A unique modulator of hippocampal synaptic information processing and cognition. Neurobiology of Learning and Memory, 138, 145–153. doi:10.1016/j.nlm.2016.06.014.
    1. Hille, C., Bate, S., Davis, J., & Gonzalez, M. I. (2008). 5-HT4 Receptor agonism in the five-choice serial reaction time task. Behavioural Brain Research, 195(1), 180–186. doi:10.1016/j.bbr.2008.08.007.
    1. Hyman, S. E. (2012). Revolution stalled. Science Translational Medicine, 4(155), 155cm111. doi:10.1126/scitranslmed.3003142.
    1. Idres, S., Delarue, C., Lefebvre, H., & Vaudry, H. (1991). Benzamide derivatives provide evidence for the involvement of a 5-HT4 receptor type in the mechanism of action of serotonin in frog adrenocortical cells. Brain Research: Molecular Brain Research, 10(3), 251–258. doi:10.1016/0169-328x(91)90068-9.
    1. Imoto, Y., Kira, T., Sukeno, M., Nishitani, N., Nagayasu, K., Nakagawa, T., … Segi-Nishida, E. (2015). Role of the 5-HT4 receptor in chronic fluoxetine treatment-induced neurogenic activity and granule cell dematuration in the dentate gyrus. Molecular Brain, 8, 29. doi:10.1186/s13041-015-0120-3.
    1. Ishizuka, T., Goshima, H., Ozawa, A., & Watanabe, Y. (2014). Stimulation of 5-HT4 receptor enhances differentiation of mouse induced pluripotent stem cells into neural progenitor cells. Clinical and Experimental Pharmacology and Physiology, 41(5), 345–350. doi:10.1111/1440-1681.12224.
    1. Johnson, D. E., Drummond, E., Grimwood, S., Sawant-Basak, A., Miller, E., Tseng, E., … Siok, C. J. (2012). The 5-hydroxytryptamine4 receptor agonists prucalopride and PRX-03140 increase acetylcholine and histamine levels in the rat prefrontal cortex and the power of stimulated hippocampal theta oscillations. Journal of Pharmacology and Experimental Therapeutics, 341(3), 681–691. doi:10.1124/jpet.112.192351.
    1. Kanzari, A., Bourcier-Lucas, C., Freyssin, A., Abrous, D. N., Haddjeri, N., & Lucas, G. (2018). Inducing a long-term potentiation in the dentate gyrus is sufficient to produce rapid antidepressant-like effects. Molecular Psychiatry, 23(3), 587–596. doi:10.1038/mp.2017.94.
    1. Kaumann, A. J. (1990). Piglet sinoatrial 5-HT receptors resemble human atrial 5-HT4-like receptors. Naunyn-Schmiedebergs Archives of Pharmacology, 342(5), 619–622. doi:10.1007/bf00169055.
    1. Kemp, A., & Manahan-Vaughan, D. (2005). The 5-hydroxytryptamine4 receptor exhibits frequency-dependent properties in synaptic plasticity and behavioural metaplasticity in the hippocampal CA1 region in vivo. Cerebral Cortex, 15(7), 1037–1043. doi:10.1093/cercor/bhh204.
    1. Kennett, G. A., Bright, F., Trail, B., Blackburn, T. P., & Sanger, G. J. (1997). Anxiolytic-like actions of the selective 5-HT4 receptor antagonists SB 204070A and SB 207266A in rats. Neuropharmacology, 36(4-5), 707–712. doi:10.1016/s0028-3908(97)00037-3.
    1. King, M. V., Marsden, C. A., & Fone, K. C. (2008). A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory. Trends in Pharmacological Sciences, 29(9), 482–492.
    1. Kobayashi, K., Ikeda, Y., Sakai, A., Yamasaki, N., Haneda, E., Miyakawa, T., & Suzuki, H. (2010). Reversal of hippocampal neuronal maturation by serotonergic antidepressants. Proceedings of the National Academy of Sciences of the United States of America, 107(18), 8434–8439. doi:10.1073/pnas.0912690107.
    1. Kulla, A., & Manahan-Vaughan, D. (2002). Modulation by serotonin 5-HT(4) receptors of long-term potentiation and depotentiation in the dentate gyrus of freely moving rats. Cerebral Cortex, 12(2), 150–162. doi:10.1093/cercor/12.2.150.
    1. Lamirault, L., Guillou, C., Thal, C., & Simon, H. (2003). Combined treatment with galanthaminium bromide, a new cholinesterase inhibitor, and RS 67333, a partial agonist of 5-HT4 receptors, enhances place and object recognition in young adult and old rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 27(1), 185–195. doi:10.1016/s0278-5846(02)00351-2.
    1. Lamirault, L., & Simon, H. (2001). Enhancement of place and object recognition memory in young adult and old rats by RS 67333, a partial agonist of 5-HT4 receptors. Neuropharmacology, 41(7), 844–853.
    1. Lelong, V., Dauphin, F., & Boulouard, M. (2001). RS 67333 And D-cycloserine accelerate learning acquisition in the rat. Neuropharmacology, 41(4), 517–522.
    1. Letty, S., Child, R., Dumuis, A., Pantaloni, A., Bockaert, J., & Rondouin, G. (1997). 5-HT4 receptors improve social olfactory memory in the rat. Neuropharmacology, 36(4-5), 681–687.
    1. Levallet, G., Hotte, M., Boulouard, M., & Dauphin, F. (2009). Increased particulate phosphodiesterase 4 in the prefrontal cortex supports 5-HT4 receptor-induced improvement of object recognition memory in the rat. Psychopharmacology, 202(1–3), 125–139. doi:10.1007/s00213-008-1283-8.
    1. Licht, C. L., Kirkegaard, L., Zueger, M., Chourbaji, S., Gass, P., Aznar, S., & Knudsen, G. M. (2010). Changes in 5-HT4 receptor and 5-HT transporter binding in olfactory bulbectomized and glucocorticoid receptor heterozygous mice. Neurochemistry International, 56(4), 603–610. doi:10.1016/j.neuint.2010.01.003.
    1. Licht, C. L., Marcussen, A. B., Wegener, G., Overstreet, D. H., Aznar, S., & Knudsen, G. M. (2009). The brain 5-HT4 receptor binding is down-regulated in the flinders sensitive line depression model and in response to paroxetine administration. Journal of Neurochemistry, 109(5), 1363–1374. doi:10.1111/j.1471-4159.2009.06050.x.
    1. Lo, A. C., De Maeyer, J. H., Vermaercke, B., Callaerts-Vegh, Z., Schuurkes, J. A., & D'Hooge, R. (2014). SSP-002392, a new 5-HT4 receptor agonist, dose-dependently reverses scopolamine-induced learning and memory impairments in C57Bl/6 mice. Neuropharmacology, 85, 178–189. doi:10.1016/j.neuropharm.2014.05.013.
    1. Lucas, G., Compan, V., Charnay, Y., Neve, R. L., Nestler, E. J., Bockaert, J., … Debonnel, G. (2005). Frontocortical 5-HT4 receptors exert positive feedback on serotonergic activity: Viral transfections, subacute and chronic treatments with 5-HT4 agonists. Biological Psychiatry, 57(8), 918–925. doi:10.1016/j.biopsych.2004.12.023.
    1. Lucas, G., & Debonnel, G. (2002). 5-HT4 Receptors exert a frequency-related facilitatory control on dorsal raphé nucleus 5-HT neuronal activity. European Journal of Neuroscience, 16(5), 817–822.
    1. Lucas, G., Du, J., Romeas, T., Mnie-Filali, O., Haddjeri, N., Piñeyro, G., & Debonnel, G. (2010). Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the Rat. PLoS ONE, 5(2):e9253.
    1. Lucas, G., Rymar, V. V., Du, J., Mnie-Filali, O., Bisgaard, C., Manta, S., … Debonnel, G. (2007). Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron, 55(5), 712–725. doi:10.1016/j.neuron.2007.07.041.
    1. Madsen, K., Torstensen, E., Holst, K. K., Haahr, M. E., Knorr, U., Frokjaer, V. G., … Knudsen, G. M. (2014). Familial risk for major depression is associated with lower striatal 5-HT(4) receptor binding. International Journal of Neuropsychopharmacology, 18(1) pii: pyu034. doi:10.1093/ijnp/pyu034.
    1. Malberg, J. E., Eisch, A. J., Nestler, E. J., & Duman, R. S. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Journal of Neuroscience, 20(24), 9104–9110.
    1. Marchetti-Gauthier, E., Roman, F. S., Dumuis, A., Bockaert, J., & Soumireu-Mourat, B. (1997). BIMU1 Increases associative memory in rats by activating 5-HT4 receptors. Neuropharmacology, 36(4–5), 697–706.
    1. Marchetti, E., Chaillan, F. A., Dumuis, A., Bockaert, J., Soumireu-Mourat, B., & Roman, F. S. (2004). Modulation of memory processes and cellular excitability in the dentate gyrus of freely moving rats by a 5-HT4 receptors partial agonist, and an antagonist. Neuropharmacology, 47(7), 1021–1035. doi:10.1016/j.neuropharm.2004.06.033.
    1. Marchetti, E., Dumuis, A., Bockaert, J., Soumireu-Mourat, B., & Roman, F. S. (2000). Differential modulation of the 5-HT(4) receptor agonists and antagonist on rat learning and memory. Neuropharmacology, 39(11), 2017–2027. doi:10.1016/s0028-3908(00)00038-1.
    1. Marchetti, E., Jacquet, M., Escoffier, G., Miglioratti, M., Dumuis, A., Bockaert, J., & Roman, F. S. (2011). Enhancement of reference memory in aged rats by specific activation of 5-HT(4) receptors using an olfactory associative discrimination task. Brain Research, 1405, 49–56. doi:10.1016/j.brainres.2011.06.020.
    1. Medhurst, A. D., Lezoualc'h, F., Fischmeister, R., Middlemiss, D. N., & Sanger, G. J. (2001). Quantitative mRNA analysis of five C-terminal splice variants of the human 5-HT4 receptor in the central nervous system by TaqMan real time RT-PCR. Brain Research: Molecular Brain Research, 90(2), 125–134.
    1. Mendez-David, I., David, D. J., Darcet, F., Wu, M. V., Kerdine-Römer, S., Gardier, A. M., & Hen, R. (2014). Rapid anxiolytic effects of a 5-HT₄ receptor agonist are mediated by a neurogenesis-independent mechanism. Neuropsychopharmacology, 39(6), 1366–1378. doi:10.1038/npp.2013.332.
    1. Meneses, A., & Hong, E. (1997). Effects of 5-HT4 receptor agonists and antagonists in learning. Pharmacology, Biochemistry and Behavior, 56(3), 347–351. doi:10.1016/s0091-3057(96)00224-9.
    1. Millan, M. J., Agid, Y., Brune, M., Bullmore, E. T., Carter, C. S., Clayton, N. S., … Young, L. J. (2012). Cognitive dysfunction in psychiatric disorders: Characteristics, causes and the quest for improved therapy. Nature Reviews. Drug Discovery, 11(2), 141–168. doi:10.1038/nrd3628.
    1. Mitchell, A. J. (2006). Two-week delay in onset of action of antidepressants: New evidence. British Journal of Psychiatry, 188, 105–106. England.
    1. Moha ou Maati, H., Bourcier-Lucas, C., Veyssiere, J., Kanzari, A., Heurteaux, C., Borsotto, M., … Lucas, G. (2016). The peptidic antidepressant spadin interacts with prefrontal 5-HT(4) and mGluR(2) receptors in the control of serotonergic function. Brain Structure & Function, 221(1), 21–37. doi:10.1007/s00429-014-0890-x.
    1. Mohler, E. G., Shacham, S., Noiman, S., Lezoualc'h, F., Robert, S., Gastineau, M., … Ragozzino, M. E. (2007). VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux. Neuropharmacology, 53(4), 563–573. doi:10.1016/j.neuropharm.2007.06.016.
    1. Moser, P. C., Bergis, O. E., Jegham, S., Lochead, A., Duconseille, E., Terranova, J. P., … Scatton, B. (2002). SL65.0155, A novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties. Journal of Pharmacology and Experimental Therapeutics, 302(2), 731–741. doi:10.1124/jpet.102.034249.
    1. Murphy, S. E., Wright, L. C., Browning, M., Cowen, P. J., & Harmer, C. J. (2019). A role for 5-HT4 receptors in human learning and memory. Psychological Medicine, 1–9. doi:10.1017/s0033291719002836.
    1. Nasehi, M., Tabatabaie, M., Khakpai, F., & Zarrindast, M. R. (2015). The effects of CA1 5HT4 receptors in MK801-induced amnesia and hyperlocomotion. Neuroscience Letters, 587, 73–78. doi:10.1016/j.neulet.2014.12.019.
    1. Norman, E. D., Thiels, E., Barrionuevo, G., & Klann, E. (2000). Long-term depression in the hippocampus in vivo is associated with protein phosphatase-dependent alterations in extracellular signal-regulated kinase. Journal of Neurochemistry, 74(1), 192–198. doi:10.1046/j.1471-4159.2000.0740192.x.
    1. Ohtsuki, T., Ishiguro, H., Detera-Wadleigh, S. D., Toyota, T., Shimizu, H., Yamada, K., … Arinami, T. (2002). Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH genetics initiative bipolar pedigrees. Molecular Psychiatry, 7(9), 954–961. doi:10.1038/sj.mp.4001133.
    1. Orsetti, M., Dellarole, A., Ferri, S., & Ghi, P. (2003). Acquisition, retention, and recall of memory after injection of RS67333, a 5-HT(4) receptor agonist, into the nucleus basalis magnocellularis of the rat. Learning and Memory, 10(5), 420–426. doi:10.1101/lm.67303.
    1. Pascual-Brazo, J., Castro, E., Díaz, A., Valdizán, E. M., Pilar-Cuéllar, F., Vidal, R., … Pazos, A. (2012). Modulation of neuroplasticity pathways and antidepressant-like behavioural responses following the short-term (3 and 7 days) administration of the 5-HT₄ receptor agonist RS67333. International Journal of Neuropsychopharmacology, 15(5), 631–643. doi:10.1017/S1461145711000782.
    1. Penas-Cazorla, R., & Vilaro, M. T. (2015). Serotonin 5-HT4 receptors and forebrain cholinergic system: Receptor expression in identified cell populations. Brain Structure & Function, 220(6), 3413–3434. doi:10.1007/s00429-014-0864-z.
    1. Quiedeville, A., Boulouard, M., Hamidouche, K., Da Silva Costa-Aze, V., Nee, G., Rochais, C., & Bouet, V. (2015). Chronic activation of 5-HT4 receptors or blockade of 5-HT6 receptors improve memory performances. Behavioural Brain Research, 293, 10–17. doi:10.1016/j.bbr.2015.07.020.
    1. Rosel, P., Arranz, B., Urretavizcaya, M., Oros, M., San, L., & Navarro, M. A. (2004). Altered 5-HT2A and 5-HT4 postsynaptic receptors and their intracellular signalling systems IP3 and cAMP in brains from depressed violent suicide victims. Neuropsychobiology, 49(4), 189–195. doi:10.1159/000077365.
    1. Roychowdhury, S., Haas, H., & Anderson, E. G. (1994). 5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells. Neuropharmacology, 33(3–4), 551–557.
    1. Rush, A. J., Warden, D., Wisniewski, S. R., Fava, M., Trivedi, M. H., Gaynes, B. N., & Nierenberg, A. A. (2009). STAR*D: Revising conventional wisdom. CNS Drugs, 23(8), 627–647. doi:10.2165/00023210-200923080-00001.
    1. Samuels, B. A., Mendez-David, I., Faye, C., David, S. A., Pierz, K. A., Gardier, A. M., … David, D. J. (2016). Serotonin 1A and serotonin 4 receptors: Essential mediators of the neurogenic and behavioral actions of antidepressants. Neuroscientist, 22(1), 26–45. doi:10.1177/1073858414561303.
    1. Schmidt, E. F., Warner-Schmidt, J. L., Otopalik, B. G., Pickett, S. B., Greengard, P., & Heintz, N. (2012). Identification of the cortical neurons that mediate antidepressant responses. Cell, 149(5), 1152–1163. doi:10.1016/j.cell.2012.03.038.
    1. Segu, L., Lecomte, M. J., Wolff, M., Santamaria, J., Hen, R., Dumuis, A., … Compan, V. (2010). Hyperfunction of muscarinic receptor maintains long-term memory in 5-HT4 receptor knock-out mice. PLoS ONE, 5(3), e9529. doi:10.1371/journal.pone.0009529.
    1. Shilyansky, C., Williams, L. M., Gyurak, A., Harris, A., Usherwood, T., & Etkin, A. (2016). Effect of antidepressant treatment on cognitive impairments associated with depression: A randomised longitudinal study. The Lancet. Psychiatry, 3(5), 425–435. doi:10.1016/s2215-0366(16)00012-2.
    1. Silvestre, J. S., Fernandez, A. G., & Palacios, J. M. (1996). Effects of 5-HT4 receptor antagonists on rat behaviour in the elevated plus-maze test. European Journal of Pharmacology, 309(3), 219–222. doi:10.1016/0014-2999(96)00457-8.
    1. Siniscalchi, A., Badini, I., Beani, L., & Bianchi, C. (1999). 5-HT4 Receptor modulation of acetylcholine outflow in Guinea pig brain slices. Neuroreport, 10(3), 547–551.
    1. Terry, A. V., Jr., Buccafusco, J. J., Jackson, W. J., Prendergast, M. A., Fontana, D. J., Wong, E. H., … Eglen, R. M. (1998). Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS 17017. Psychopharmacology, 135(4), 407–415. doi:10.1007/s002130050529.
    1. Tonini, M., & Candura, S. M. (1996). 5-HT4 Receptor agonists and bladder disorders. Trends in Pharmacological Sciences, 17, 314–316. England.
    1. Trivedi, M. H., Fava, M., Wisniewski, S. R., Thase, M. E., Quitkin, F., Warden, D., … Rush, A. J. (2006). Medication augmentation after the failure of SSRIs for depression. New England Journal of Medicine, 354(12), 1243–1252. doi:10.1056/NEJMoa052964.
    1. Twarkowski, H., Hagena, H., & Manahan-Vaughan, D. (2016). The 5-hydroxytryptamine4 receptor enables differentiation of informational content and encoding in the hippocampus. Hippocampus, 26(7), 875–891. doi:10.1002/hipo.22569.
    1. Varnas, K., Halldin, C., Pike, V. W., & Hall, H. (2003). Distribution of 5-HT4 receptors in the postmortem human brain – an autoradiographic study using [125I]SB 207710. European Neuropsychopharmacology, 13(4), 228–234.
    1. Vidal, R., Valdizan, E. M., Mostany, R., Pazos, A., & Castro, E. (2009). Long-term treatment with fluoxetine induces desensitization of 5-HT4 receptor-dependent signalling and functionality in rat brain. Journal of Neurochemistry, 110(3), 1120–1127. doi:10.1111/j.1471-4159.2009.06210.x.
    1. Vidal, R., Valdizan, E., Vilaró, M., Pazos, A., & Castro, E. (2010). Reduced signal transduction by 5-HT4 receptors after long-term venlafaxine treatment in rats. British Journal of Pharmacology, 161(3), 695–706. doi:10.1111/j.1476-5381.2010.00903.x.
    1. Vilaró, M. T., Cortés, R., & Mengod, G. (2005). Serotonin 5-HT4 receptors and their mRNAs in rat and Guinea pig brain: Distribution and effects of neurotoxic lesions. Journal of Comparative Neurology, 484(4), 418–439. doi:10.1002/cne.20447.
    1. Waeber, C., Sebben, M., Nieoullon, A., Bockaert, J., & Dumuis, A. (1994). Regional distribution and ontogeny of 5-HT4 binding sites in rodent brain. Neuropharmacology, 33(3–4), 527–541. doi:10.1016/0028-3908(94)90084-1.
    1. Warner-Schmidt, J. L., & Duman, R. S. (2006). Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment. Hippocampus, 16(3), 239–249. doi:10.1002/hipo.20156.
    1. Wong, C. H., Siah, K. W., & Lo, A. W. (2019). Estimation of clinical trial success rates and related parameters. Biostatistics, 20(2), 273–286.
    1. World Health Organisation (2017). Depression and other common mental disorders. Global Health Estimates.
    1. Wray, N. R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E. M., Abdellaoui, A., … Consortium, M. D. D. W. G. O. T. P. G. (2018). Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics, 50(5), 668–681. doi:10.1038/s41588-018-0090-3.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren