Role of Serotonin-2A Receptors in Pathophysiology and Treatment of Depression

  • Lucia Moravčíková
  • Kristína Csatlósová
  • Barbora Ďurišová
  • Katarína Ondáčová
  • Michaela Pavlovičová
  • Ľubica Lacinová
  • Eliyahu Dremencov
Part of the The Receptors book series (REC, volume 32)


This chapter aims to summarize the up-to-day evidence-based biomedical knowledge on serotonin-2A (5-HT2A) receptors and their role in pathophysiology and treatment of central nervous system (CNS) disorders, with a primary focus on depression. The first paragraph provides a brief introduction to serotonin (5-HT) system and 5-HT receptors, focusing on serotonin-2 (5-HT2) family and 5-HT2A receptor specifically. The second paragraph is focused on molecular genetics of 5-HT2A receptors, polymorphism of 5-HT2A receptor (5HT2AR) gene, 5HT2AR gene epigenetic mechanisms, such as DNA methylation, and post-translational modifications of 5HT2AR messenger ribonucleic acid (mRNA), such as alternative splicing. The molecular and cellular pharmacology and physiology of 5-HT2A receptors in normal and pathological conditions are discussed in the third paragraph. The 5-HT2A receptors-acting ligands are addresses. The fourth paragraph describes the role of 5-HT receptors in the interaction between 5-HT and other neurotransmitter systems in health and in CNS disorders. The fifth and the final paragraph specifically deals with the role of 5-HT2A receptor in pathophysiology and treatment of depression, focusing on the 5-HT2A receptor expressed in the hippocampus.


Serotonin-2A receptor (5HT2AR) gene polymorphism Deoxyribonucleic acid (DNA) methylation Messenger ribonucleic acid (mRNA) alternative splicing G-protein coupled receptors (GPCR) Q/Z-11 protein Phospholipase C (PLC) Inositol trisphosphate (IP3Calcium signaling Antidepressant drugs Antipsychotic drugs Hippocampus 



The authors of this chapter were supported by the Slovak Academy of Sciences (SAS; 2013 Scholarship Award), by the Scientific Grant Agency of Ministry of Education of Slovak Republic and SAS (grants VEGA-2/0019/15 and VEGA-2/0024/15) and by the Slovak Research and Development Agency (Grants APVV-15-0388).


  1. 1.
    Leysen JE (2004) 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord 3(1):11–26PubMedCrossRefGoogle Scholar
  2. 2.
    Ishier R, Bhattacharya A, Panicker MM (2007) Serotonin-2A (5-HT2A) receptor function: ligand-dependent mechanisms and pathways. In: Chattopadhyay A (ed) Serotonin receptors in neurobiology. CRC, Boca Raton, FL, pp 105–132Google Scholar
  3. 3.
    Kroeze WK, Kristiansen K, Roth BL (2002) Molecular biology of serotonin receptors structure and function at the molecular level. Curr Top Med Chem 2(6):507–528PubMedCrossRefGoogle Scholar
  4. 4.
    Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71(4):533–554. doi:S0091305701007468 [pii]PubMedCrossRefGoogle Scholar
  5. 5.
    Van de Kar LD, Javed A, Zhang Y et al (2001) 5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells. J Neurosci 21(10):3572–3579. doi:21/10/3572 [pii]PubMedGoogle Scholar
  6. 6.
    Kleinrock M (2011) The use of medicines in the United States: review of 2010. IMS Institute for Healthcare Informatics, Danbury, CTGoogle Scholar
  7. 7.
    Becker KG, Barnes KC, Bright TJ et al (2004) The genetic association database. Nat Genet 36(5):431–432. PubMedCrossRefGoogle Scholar
  8. 8.
    Parsons MJ, D’Souza UM, Arranz MJ, Kerwin RW, Makoff AJ (2004) The -1438A/Gpolymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity. Biol Psychiatry 56(6):406–410Google Scholar
  9. 9.
    Serretti A, Drago A, De Ronchi D (2007) HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Curr Med Chem 14(19):2053–2069PubMedCrossRefGoogle Scholar
  10. 10.
    Hazelwood LA, Sanders-Bush E (2004) His452Tyr polymorphism in the human 5-HT2A receptor destabilizes the signaling conformation. Mol Pharmacol 66(5):1293–1300PubMedGoogle Scholar
  11. 11.
    Lin CX, Hu Z, Yan ZM et al (2015) Association between HTR2A T102C polymorphism and major depressive disorder: a meta-analysis in the Chinese population. Int J Clin Exp Med 8(11):20897–20903PubMedPubMedCentralGoogle Scholar
  12. 12.
    Tan J, Chen S, Su L et al (2014) Association of the T102C polymorphism in the HTR2A gene with major depressive disorder, bipolar disorder, and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 165B(5):438–455. PubMedCrossRefGoogle Scholar
  13. 13.
    Zhao X, Sun L, Sun YH et al (2014) Association of HTR2A T102C and A-1438G polymorphisms with susceptibility to major depressive disorder: a meta-analysis. Neurol Sci 35(12):1857–1866. PubMedCrossRefGoogle Scholar
  14. 14.
    Jobim PF, Prado-Lima PA, Schwanke CH et al (2008) The polymorphism of the serotonin-2A receptor T102C is associated with age. Braz J Med Biol Res 41(11):1018–1023. doi:S0100-879X2008005000045 [pii]PubMedCrossRefGoogle Scholar
  15. 15.
    Petit AC, Quesseveur G, Gressier F et al (2014) Converging translational evidence for the involvement of the serotonin 2A receptor gene in major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 54:76–82. CrossRefGoogle Scholar
  16. 16.
    Qesseveur G, Petit AC, Nguyen HT, Dahan L, Colle R, Rotenberg S, Seif I, Robert P, David D, Guilloux JP, Gardier AM, Verstuyft C, Becquemont L, Corruble E, Guiard BP (2016) Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: a translational approach. Neuropharmacology 105:142–153. PubMedCrossRefGoogle Scholar
  17. 17.
    Abdolmaleky HM, Faraone SV, Glatt SJ et al (2004) Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. Schizophr Res 67(1):53–62. doi:S092099640300183X [pii]PubMedCrossRefGoogle Scholar
  18. 18.
    Joober R, Benkelfat C, Brisebois K et al (1999) T102C polymorphism in the 5HT2A gene and schizophrenia: relation to phenotype and drug response variability. J Psychiatry Neurosci 24(2):141–146PubMedPubMedCentralGoogle Scholar
  19. 19.
    Serretti A, Benedetti F, Mandelli L et al (2008) Association between GSK-3beta -50T/C polymorphism and personality and psychotic symptoms in mood disorders. Psychiatry Res 158(2):132–140. doi:S0165-1781(07)00199-0 [pii]PubMedCrossRefGoogle Scholar
  20. 20.
    do Prado-Lima PA, Chatkin JM, Taufer M et al (2004) Polymorphism of 5HT2A serotonin receptor gene is implicated in smoking addiction. Am J Med Genet B Neuropsychiatr Genet 128B(1):90–93.
  21. 21.
    Nakamura T, Matsushita S, Nishiguchi N et al (1999) Association of a polymorphism of the 5HT2A receptor gene promoter region with alcohol dependence. Mol Psychiatry 4(1):85–88PubMedCrossRefGoogle Scholar
  22. 22.
    Craig D, Donnelly C, Hart D et al (2007) Analysis of the 5HT-2A T102C receptor polymorphism and psychotic symptoms in Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 144B(1):126–128. PubMedCrossRefGoogle Scholar
  23. 23.
    Lam LC, Tang NL, Ma SL et al (2004) 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer’s disease. Int J Geriatr Psychiatry 19(6):523–526. PubMedCrossRefGoogle Scholar
  24. 24.
    Polesskaya OO, Aston C, Sokolov BP (2006) Allele C-specific methylation of the 5-HT2A receptor gene: evidence for correlation with its expression and expression of DNA methylase DNMT1. J Neurosci Res 83(3):362–373. PubMedCrossRefGoogle Scholar
  25. 25.
    De Luca V, Viggiano E, Dhoot R et al (2009) Methylation and QTDT analysis of the 5-HT2A receptor 102C allele: analysis of suicidality in major psychosis. J Psychiatr Res 43(5):532–537.
  26. 26.
    Falkenberg VR, Gurbaxani BM, Unger ER et al (2011) Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. Neuromol Med 13(1):66–76.
  27. 27.
    Huang X, Xiao H, Rex EB et al (2002) Functional characterization of alternatively spliced 5-HT2 receptor isoforms from the pharynx and muscle of the parasitic nematode, Ascaris suum. J Neurochem 83(2):249–258. doi:1067 [pii]PubMedCrossRefGoogle Scholar
  28. 28.
    Guest PC, Salim K, Skynner HA et al (2000) Identification and characterization of a truncated variant of the 5-hydroxytryptamine(2A) receptor produced by alternative splicing. Brain Res 876(1–2):238–244. doi:S0006-8993(00)02664-0 [pii]PubMedCrossRefGoogle Scholar
  29. 29.
    Berg KA, Maayani S, Goldfarb J et al (1998a) Pleiotropic behavior of 5-HT2A and 5-HT2C receptor agonists. Ann N Y Acad Sci 861:104–110PubMedCrossRefGoogle Scholar
  30. 30.
    Hoyer D, Clarke DE, Fozard JR et al (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 46(2):157–203PubMedGoogle Scholar
  31. 31.
    Raymond JR, Mukhin YV, Gelasco A et al (2001) Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 92(2-3):179–212. doi:S0163725801001693 [pii]PubMedCrossRefGoogle Scholar
  32. 32.
    Gooz M, Gooz P, Luttrell LM et al (2006) 5-HT2A receptor induces ERK phosphorylation and proliferation through ADAM-17 tumor necrosis factor-alpha-converting enzyme (TACE) activation and heparin-bound epidermal growth factor-like growth factor (HB-EGF) shedding in mesangial cells. J Biol Chem 281(30):21004–21012. doi:M512096200 [pii]PubMedCrossRefGoogle Scholar
  33. 33.
    Quinn JC, Johnson-Farley NN, Yoon J et al (2002) Activation of extracellular-regulated kinase by 5-hydroxytryptamine(2A) receptors in PC12 cells is protein kinase C-independent and requires calmodulin and tyrosine kinases. J Pharmacol Exp Ther 303(2):746–752. PubMedCrossRefGoogle Scholar
  34. 34.
    Sheffler DJ, Kroeze WK, Garcia BG et al (2006) p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling. Proc Natl Acad Sci U S A 103(12):4717–4722. doi:0600585103 [pii]PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Strachan RT, Allen JA, Sheffler DJ et al (2010) p90 Ribosomal S6 kinase 2, a novel GPCR kinase, is required for growth factor-mediated attenuation of GPCR signaling. Biochemistry 49(12):2657-2671.
  36. 36.
    Strachan RT, Sheffler DJ, Willard B et al (2009) Ribosomal S6 kinase 2 directly phosphorylates the 5-hydroxytryptamine 2A (5-HT2A) serotonin receptor, thereby modulating 5-HT2A signaling. J Biol Chem 284(9):5557–5573. PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Arranz MJ, Munro J, Owen MJ et al (1998) Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry 3(1):61–66PubMedCrossRefGoogle Scholar
  38. 38.
    Dai Y, Dudek NL, Patel TB et al (2008) Transglutaminase-catalyzed transamidation: a novel mechanism for Rac1 activation by 5-hydroxytryptamine2A receptor stimulation. J Pharmacol Exp Ther 326(1):153–162. PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Singh RK, Jia C, Garcia F et al (2010) Activation of the JAK-STAT pathway by olanzapine is necessary for desensitization of serotonin2A receptor-stimulated phospholipase C signaling in rat frontal cortex but not serotonin2A receptor-stimulated hormone release. J Psychopharmacol 24(7):1079–1088. PubMedCrossRefGoogle Scholar
  40. 40.
    Shi J, Damjanoska KJ, Singh RK et al (2007) Agonist induced-phosphorylation of Galpha11 protein reduces coupling to 5-HT2A receptors. J Pharmacol Exp Ther 323(1):248–256. doi:jpet.107.122317 [pii]PubMedCrossRefGoogle Scholar
  41. 41.
    Kurrasch-Orbaugh DM, Watts VJ, Barker EL et al (2003) Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves. J Pharmacol Exp Ther 304(1):229–237. PubMedCrossRefGoogle Scholar
  42. 42.
    Berg KA, Maayani S, Goldfarb J et al (1998b) Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol 54(1):94–104PubMedCrossRefGoogle Scholar
  43. 43.
    Karaki S, Becamel C, Murat S et al (2014) Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists. Mol Cell Proteomics 13(5):1273–1285.
  44. 44.
    Jones KA, Srivastava DP, Allen JA et al (2009) Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc Natl Acad Sci U S A 106(46):19575–19580. PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Preedy VR (2016) Neuropathology of drug addictions and substance misuse, 1st edn. Elsevier B.V., Amsterdam, The NetherlandsGoogle Scholar
  46. 46.
    Bhatnagar A, Willins DL, Gray JA et al (2001) The dynamin-dependent, arrestin-independent internalization of 5-hydroxytryptamine 2A (5-HT2A) serotonin receptors reveals differential sorting of arrestins and 5-HT2A receptors during endocytosis. J Biol Chem 276(11):8269–8277. PubMedCrossRefGoogle Scholar
  47. 47.
    Bhattacharyya S (2005) Internalization and recycling of the serotonin 2A receptor in non-neuronal and neuronal cells, in National Centre for Biological Sciences. Manipal Academy of Higher Education of Bangalore, BangaloreGoogle Scholar
  48. 48.
    Barbas D, DesGroseillers L, Castellucci VF et al (2003) Multiple serotonergic mechanisms contributing to sensitization in aplysia: evidence of diverse serotonin receptor subtypes. Learn Mem 10(5):373–386. PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Citrome L, Stensbol TB, Maeda K (2015) The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders? Expert Rev Neurother 15(10):1219–1229. PubMedCrossRefGoogle Scholar
  50. 50.
    Ishima T, Futamura T, Ohgi Y et al (2015) Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin-dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT2A receptors. Eur Neuropsychopharmacol 25(4):505–511. PubMedCrossRefGoogle Scholar
  51. 51.
    Boothman LJ, Allers KA, Rasmussen K, Sharp T. Evidence that central 5-HT2A and 5-HT2B/C receptors regulate 5-HT cell firing in the dorsal raphe nucleus of the anaesthetised rat. Br J Pharmacol. 2003;139(5):998-1004. Erratum in: Br J Pharmacol. 2003;140(1):227–8.Google Scholar
  52. 52.
    Quesseveur G, Repérant C, David DJ, Gardier AM, Sanchez C, Guiard BP (2013) 5-HT2A receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system. Exp Brain Res 226(2):285–295. PubMedCrossRefGoogle Scholar
  53. 53.
    Puig MV, Celada P, Diaz-Mataix L et al (2003) In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors: relationship to thalamocortical afferents. Cereb Cortex 13(8):870–882PubMedCrossRefGoogle Scholar
  54. 54.
    Bortolozzi A, Amargos-Bosch M, Adell A et al (2003) In vivo modulation of 5-hydroxytryptamine release in mouse prefrontal cortex by local 5-HT(2A) receptors: effect of antipsychotic drugs. Eur J Neurosci 18(5):1235–1246. doi:2829 [pii]PubMedCrossRefGoogle Scholar
  55. 55.
    Celada P, Puig MV, Casanovas JM et al (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci 21(24):9917–9929PubMedGoogle Scholar
  56. 56.
    Groenewegen HJ, Uylings HB (2000) The prefrontal cortex and the integration of sensory, limbic and autonomic information. Prog Brain Res 126:3–28. doi:S0079-6123(00)26003-2 [pii]PubMedCrossRefGoogle Scholar
  57. 57.
    Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F (2005) The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem 95(6):1597–1607PubMedCrossRefGoogle Scholar
  58. 58.
    Miner LA, Backstrom JR, Sanders-Bush E et al (2003) Ultrastructural localization of serotonin2A receptors in the middle layers of the rat prelimbic prefrontal cortex. Neuroscience 116(1):107–117. doi:S0306452202005808 [pii]PubMedCrossRefGoogle Scholar
  59. 59.
    Ichikawa J, Dai J, Meltzer HY (2001) DOI, a 5-HT2A/2C receptor agonist, attenuates clozapine-induced cortical dopamine release. Brain Res 907(1-2):151–155. doi:S0006-8993(01)02596-3 [pii]PubMedCrossRefGoogle Scholar
  60. 60.
    Pehek EA, McFarlane HG, Maguschak K et al (2001) M100,907, a selective 5-HT(2A) antagonist, attenuates dopamine release in the rat medial prefrontal cortex. Brain Res 888(1):51–59. doi:S0006-8993(00)03004-3 [pii]PubMedCrossRefGoogle Scholar
  61. 61.
    Lucas G, Spampinato U (2000) Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum. J Neurochem 74(2):693–701PubMedCrossRefGoogle Scholar
  62. 62.
    Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, Höschl C (2006) Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 20(5):389–409PubMedCrossRefGoogle Scholar
  63. 63.
    Maeda K, Lerdrup L, Sugino H et al (2014a) Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther 350(3):605–614. PubMedCrossRefGoogle Scholar
  64. 64.
    Maeda K, Sugino H, Akazawa H et al (2014b) Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther 350(3):589–604.
  65. 65.
    Burris KD, Molski TF, Xu C et al (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302(1):381–389PubMedCrossRefGoogle Scholar
  66. 66.
    Guiard BP, El Mansari M, Merali Z, Blier P (2008) Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. Int J Neuropsychopharmacol 11(5):625–639. PubMedCrossRefGoogle Scholar
  67. 67.
    Dremencov E, El Mansari M, Blier P (2009) Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci 34(3):223–229Google Scholar
  68. 68.
    Szabo ST, Blier P (2001) Effect of the selective noradrenergic reuptake inhibitor reboxetine on the firing activity of noradrenaline and serotonin neurons. Eur J Neurosci 13(11):2077–2087PubMedCrossRefGoogle Scholar
  69. 69.
    Szabo ST, Blier P (2002) Effects of serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibition plus 5-HT(2A) receptor antagonism on the firing activity of norepinephrine neurons. J Pharmacol Exp Ther 302(3):983–991PubMedCrossRefGoogle Scholar
  70. 70.
    Oosterhof CA, El Mansari M, Blier P (2014) Acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine systems: an in vivo electrophysiologic characterization. J Pharmacol Exp Ther 351(3):585–595. PubMedCrossRefGoogle Scholar
  71. 71.
    Dremencov E, El Mansari M, Blier P (2007b) Noradrenergic augmentation of escitalopram response by risperidone: electrophysiologic studies in the rat brain. Biol Psychiatry 61(5):671–678. S0006-3223(06)00659-7 [pii];
  72. 72.
    Marek GJ, Carpenter LL, McDougle CJ et al (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28(2):402–412. PubMedCrossRefGoogle Scholar
  73. 73.
    Schotte A, Janssen PF, Gommeren W et al (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124(1-2):57–73PubMedCrossRefGoogle Scholar
  74. 74.
    Dhir A, Kulkarni SK (2008) Risperidone, an atypical antipsychotic enhances the antidepressant-like effect of venlafaxine or fluoxetine: possible involvement of alpha-2 adrenergic receptors. Neurosci Lett 445(1):83–88.
  75. 75.
    Dremencov E, El Mansari M, Blier P (2007a) Distinct electrophysiological effects of paliperidone and risperidone on the firing activity of rat serotonin and norepinephrine neurons. Psychopharmacology.
  76. 76.
    Bianchetti A, Manara L (1990) In vitro inhibition of intestinal motility by phenylethanolaminotetralines: evidence of atypical beta-adrenoceptors in rat colon. Br J Pharmacol 100(4):831–839PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Overstreet DH, Stemmelin J, Griebel G (2008) Confirmation of antidepressantpotential of the selective beta3 adrenoceptor agonist amibegron in an animal model of depression. Pharmacol Biochem Behav 89(4):623–626. PubMedCrossRefGoogle Scholar
  78. 78.
    Claustre Y, Leonetti M, Santucci V et al (2008) Effects of the beta3-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: relevance to its antidepressant/anxiolytic-like profile. Neuroscience 156(2):353–364.
  79. 79.
    Tanyeri P, Buyukokuroglu ME, Mutlu O et al (2013a) Evidence that the anxiolytic-like effects of the beta3 receptor agonist amibegron involve serotoninergic receptor activity. Pharmacol Biochem Behav 110:27–32.
  80. 80.
    Tanyeri P, Buyukokuroglu ME, Mutlu O et al (2013b) Involvement of serotonin receptor subtypes in the antidepressant-like effect of beta receptor agonist Amibegron (SR 58611A): an experimental study. Pharmacol Biochem Behav 105:12–16. PubMedCrossRefGoogle Scholar
  81. 81.
    Weisstaub NV, Zhou M, Lira A, Lambe E, González-Maeso J, Hornung JP, Sibille E, Underwood M, Itohara S, Dauer WT, Ansorge MS, Morelli E, Mann JJ, Toth M, Aghajanian G, Sealfon SC, Hen R, Gingrich JA (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313(5786):536–540PubMedCrossRefGoogle Scholar
  82. 82.
    Morici JF, Ciccia L, Malleret G, Gingrich JA, Bekinschtein P, Weisstaub NV (2015) Serotonin 2a receptor and Serotonin 1a receptor interact within the medial prefrontal cortex during recognition memory in mice. Front Pharmacol 6:298. eCollection 2015PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    de Quervain DJ, Henke K, Aerni A et al (2003) A functional genetic variation of the 5-HT2a receptor affects human memory. Nat Neurosci 6(11):1141–1142. PubMedCrossRefGoogle Scholar
  84. 84.
    Lai MK, Tsang SW, Alder JT et al (2005) Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology 179(3):673–677.
  85. 85.
    Versijpt J, Van Laere KJ, Dumont F et al (2003) Imaging of the 5-HT2A system: age-, gender-, and Alzheimer’s disease-related findings. Neurobiol Aging 24(4):553-561. doi:S0197458002001379 [pii].Google Scholar
  86. 86.
    Dean B (2003) The cortical serotonin2A receptor and the pathology of schizophrenia: a likely accomplice. J Neurochem 85(1):1–13. doi:1693 [pii]PubMedCrossRefGoogle Scholar
  87. 87.
    Meltzer HY, Li Z, Kaneda Y et al (2003) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 27(7):1159–1172. doi:S0278-5846(03)00223-9 [pii]CrossRefGoogle Scholar
  88. 88.
    Roth BL, Hanizavareh SM, Blum AE (2004) Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology 174(1):17–24. PubMedCrossRefGoogle Scholar
  89. 89.
    Burnet PW, Eastwood SL, Harrison PJ (1994) Detection and quantitation of 5-HT1A and 5-HT2A receptor mRNAs in human hippocampus using a reverse transcriptase-polymerase chain reaction (RT-PCR) technique and their correlation with binding site densities and age. Neurosci Lett 178(1):85–89. doi:0304-3940(94)90296-8 [pii]PubMedCrossRefGoogle Scholar
  90. 90.
    Wright DE, Seroogy KB, Lundgren KH et al (1995) Comparative localization of serotonin1A, 1C, and 2 receptor subtype mRNAs in rat brain. J Comp Neurol 351(3):357–373. PubMedCrossRefGoogle Scholar
  91. 91.
    Pazos A, Cortes R, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346(2):231–249. doi:0006-8993(85)90857-1 [pii]PubMedCrossRefGoogle Scholar
  92. 92.
    Bombardi C (2012) Neuronal localization of 5-HT2A receptor immunoreactivity in the rat hippocampal region. Brain Res Bull 87(2-3):259–273. PubMedCrossRefGoogle Scholar
  93. 93.
    Cornea-Hebert V, Riad M, Wu C et al (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409(2):187–209.;2-P [pii]. PubMedCrossRefGoogle Scholar
  94. 94.
    Luttgen M, Ove Ogren S, Meister B (2004) Chemical identity of 5-HT2A receptor immunoreactive neurons of the rat septal complex and dorsal hippocampus. Brain Res 1010(1–2):156–165. PubMedCrossRefGoogle Scholar
  95. 95.
    Xu T, Pandey SC (2000) Cellular localization of serotonin(2A) (5HT(2A)) receptors in the rat brain. Brain Res Bull 51(6):499–505. doi:S0361-9230(99)00278-6 [pii]PubMedCrossRefGoogle Scholar
  96. 96.
    Uneyama H, Munakata M, Akaike N (1992) 5-HT response of rat hippocampal pyramidal cell bodies. Neuroreport 3(7):633–636PubMedCrossRefGoogle Scholar
  97. 97.
    Guo JD, Rainnie DG (2010) Presynaptic 5-HT(1B) receptor-mediated serotonergic inhibition of glutamate transmission in the bed nucleus of the stria terminalis. Neuroscience 165(4):1390–1401. PubMedCrossRefGoogle Scholar
  98. 98.
    Hashimoto K, Kita H (2008) Serotonin activates presynaptic and postsynaptic receptors in rat globus pallidus. J Neurophysiol 99(4):1723–1732. PubMedCrossRefGoogle Scholar
  99. 99.
    Piguet P, Galvan M (1994) Transient and long-lasting actions of 5-HT on rat dentate gyrus neurones in vitro. J Physiol 481(Pt 3):629–639Google Scholar
  100. 100.
    Shen RY, Andrade R (1998) 5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. J Pharmacol Exp Ther 285(2):805–812PubMedGoogle Scholar
  101. 101.
    Kulkarni VA, Jha S, Vaidya VA (2002) Depletion of norepinephrine decreases the proliferation, but does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus. Eur J Neurosci 16(10):2008–2012PubMedCrossRefGoogle Scholar
  102. 102.
    Ge S, Goh EL, Sailor KA et al (2006) GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439(7076):589–593. doi:nature04404 [pii]PubMedCrossRefGoogle Scholar
  103. 103.
    Banasr M, Hery M, Printemps R et al (2004) Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29(3):450–460. PubMedCrossRefGoogle Scholar
  104. 104.
    Wang RY, Arvanov VL (1998) M100907, a highly selective 5-HT2A receptor antagonist and a potential atypical antipsychotic drug, facilitates induction of long-term potentiation in area CA1 of the rat hippocampal slice. Brain Res 779(1-2):309–313. doi:S0006-8993(97)01174-8 [pii]PubMedCrossRefGoogle Scholar
  105. 105.
    Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience 124(1):71–79PubMedCrossRefGoogle Scholar
  106. 106.
    Figurov A, Pozzo-Miller LD, Olafsson P et al (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381(6584):706–709. PubMedCrossRefGoogle Scholar
  107. 107.
    Kang H, Schuman EM (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267(5204):1658–1662PubMedCrossRefGoogle Scholar
  108. 108.
    Korte M, Carroll P, Wolf E et al (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92(19):8856–8860PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Levine ES, Dreyfus CF, Black IB et al (1995) Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A 92(17):8074–8077PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Patterson SL, Abel T, Deuel TA et al (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16(6):1137–1145. doi:S0896-6273(00)80140-3 [pii]PubMedCrossRefGoogle Scholar
  111. 111.
    Vaidya VA, Marek GJ, Aghajanian GK et al (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 17(8):2785–2795PubMedGoogle Scholar
  112. 112.
    Zhang G, Asgeirsdottir HN, Cohen SJ et al (2013) Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology 64:403–413. PubMedCrossRefGoogle Scholar
  113. 113.
    Zhang G, Stackman RW Jr (2015) The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 6:225.
  114. 114.
    Peddie CJ, Davies HA, Colyer FM et al (2008) Colocalisation of serotonin2A receptors with the glutamate receptor subunits NR1 and GluR2 in the dentate gyrus: an ultrastructural study of a modulatory role. Exp Neurol 211(2):561–573. PubMedCrossRefGoogle Scholar
  115. 115.
    Aghajanian GK, Marek GJ (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21(2 Suppl):16S-23S.
  116. 116.
    Hill AS, Sahay A, Hen R (2015) Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors. Neuropsychopharmacology. 40(10):2368–2378. PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Reagan LP, McEwen BS (1997) Controversies surrounding glucocorticoid-mediated cell death in the hippocampus. J Chem Neuroanat 13(3):149–167. doi:S0891061897000318 [pii]PubMedCrossRefGoogle Scholar
  118. 118.
    Cheetham SC, Crompton MR, Katona CL et al (1988) Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res 443(1-2):272–280. doi:0006-8993(88)91621-6 [pii]PubMedCrossRefGoogle Scholar
  119. 119.
    Rosel P, Arranz B, Vallejo J et al (1998) Variations in [3H]imipramine and 5-HT2A but not [3H]paroxetine binding sites in suicide brains. Psychiatry Res 82(3):161–170PubMedCrossRefGoogle Scholar
  120. 120.
    MacQueen GM, Campbell S, McEwen BS et al (2003) Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A 100(3):1387–1392. PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Sheline YI, Sanghavi M, Mintun MA et al (1999) Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19(12):5034–5043PubMedGoogle Scholar
  122. 122.
    Sheline YI, Wang PW, Gado MH et al (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 93(9):3908–3913PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Mintun MA, Sheline YI, Moerlein SM et al (2004) Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography. Biol Psychiatry 55(3):217–224. doi:S000632230300920X [pii]PubMedCrossRefGoogle Scholar
  124. 124.
    Meltzer HY, Maes M (1995) Effect of pindolol pretreatment on MK-212-induced plasma cortisol and prolactin responses in normal men. Biol Psychiatry. 38(5):310–318PubMedCrossRefGoogle Scholar
  125. 125.
    Massou JM, Trichard C, Attar-Levy D et al (1997) Frontal 5-HT2A receptors studied in depressive patients during chronic treatment by selective serotonin reuptake inhibitors. Psychopharmacology 133(1):99–101PubMedCrossRefGoogle Scholar
  126. 126.
    Meyer JH, Kapur S, Eisfeld B et al (2001) The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am J Psychiatry 158(1):78–85. PubMedCrossRefGoogle Scholar
  127. 127.
    Meyer JH, Kapur S, Houle S et al (1999) Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study. Am J Psychiatry 156(7):1029–1034. PubMedGoogle Scholar
  128. 128.
    Yatham LN, Liddle PF, Shiah IS et al (2001) Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study. Br J Psychiatry 178:448–453PubMedCrossRefGoogle Scholar
  129. 129.
    Zanardi R, Artigas F, Moresco R et al (2001) Increased 5-hydroxytryptamine-2 receptor binding in the frontal cortex of depressed patients responding to paroxetine treatment: a positron emission tomography scan study. J Clin Psychopharmacol 21(1):53–58PubMedCrossRefGoogle Scholar
  130. 130.
    Banasr M, Chowdhury GM, Terwilliger R et al (2010) Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psychiatry 15(5):501–511. PubMedCrossRefGoogle Scholar
  131. 131.
    Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26(10):523–530. doi:S0166-2236(03)00266-2 [pii]PubMedCrossRefGoogle Scholar
  132. 132.
    Althaus HH, Richter-Landsberg C (2000) Glial cells as targets and producers of neurotrophins. Int Rev Cytol 197:203–277PubMedCrossRefGoogle Scholar
  133. 133.
    Friedman WJ, Black IB, Kaplan DR (1998) Distribution of the neurotrophins brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 in the postnatal rat brain: an immunocytochemical study. Neuroscience 84(1):101–114. doi:S0306-4522(97)00526-5 [pii]PubMedCrossRefGoogle Scholar
  134. 134.
    Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54(7):597–606PubMedCrossRefGoogle Scholar
  135. 135.
    Russo-Neustadt AA, Chen MJ (2005) Brain-derived neurotrophic factor and antidepressant activity. Curr Pharm Des 11(12):1495–1510PubMedCrossRefGoogle Scholar
  136. 136.
    Allaman I, Belanger M, Magistretti PJ (2011) Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34(2):76–87. PubMedCrossRefGoogle Scholar
  137. 137.
    Mercier G, Lennon AM, Renouf B et al (2004) MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes. J Mol Neurosci 24(2):207–216. doi:JMN:24:2:207 [pii]Google Scholar
  138. 138.
    Tsuchioka M, Takebayashi M, Hisaoka K et al (2008) Serotonin (5-HT) induces glial cell line-derived neurotrophic factor (GDNF) mRNA expression via the transactivation of fibroblast growth factor receptor 2 (FGFR2) in rat C6 glioma cells. J Neurochem 106(1):244–257.
  139. 139.
    David DJ, Wang J, Samuels BA et al (2010) Implications of the functional integration of adult-born hippocampal neurons in anxiety-depression disorders. Neuroscientist 16(5):578–591. PubMedCrossRefGoogle Scholar
  140. 140.
    Rocha BA, Scearce-Levie K, Lucas JJ et al (1998) Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor. Nature 393(6681):175–178. PubMedCrossRefGoogle Scholar
  141. 141.
    Selemon LD, Lidow MS, Goldman-Rakic PS (1999) Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure. Biol Psychiatry 46(2):161–172. doi:S0006-3223(99)00113-4 [pii]PubMedCrossRefGoogle Scholar
  142. 142.
    Czeh B, Simon M, Schmelting B et al (2006) Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology 31(8):1616–1626. doi:1300982 [pii]PubMedCrossRefGoogle Scholar
  143. 143.
    Galeotti N, Ghelardini C (2012) Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation. Int J Neuropsychopharmacol 15(6):781–793. PubMedCrossRefGoogle Scholar
  144. 144.
    Yuan P, Zhou R, Wang Y et al (2010) Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord 124(1–2):164–169. PubMedCrossRefGoogle Scholar
  145. 145.
    Gourley SL, Wu FJ, Kiraly DD et al (2008) Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiatry 63(4):353–359. doi:S0006-3223(07)00713-5 [pii]PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Lucia Moravčíková
    • 1
  • Kristína Csatlósová
    • 1
  • Barbora Ďurišová
    • 1
  • Katarína Ondáčová
    • 1
  • Michaela Pavlovičová
    • 1
  • Ľubica Lacinová
    • 1
  • Eliyahu Dremencov
    • 1
    • 2
  1. 1.Institute of Molecular Physiology and Genetics, Slovak Academy of SciencesBratislavaSlovakia
  2. 2.Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of SciencesBratislavaSlovakia

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