Brain Circuits Regulated by the 5-HT2A Receptor: Behavioural Consequences on Anxiety and Fear Memory

Chapter
Part of the The Receptors book series (REC, volume 32)

Abstract

Anxiety disorders including generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD) or phobias are the most prevalent mental pathologies across the world with a median lifetime prevalence of approximately 15%. Anxiety imposes substantial economic costs which are among the highest of all mental disorders studied. Evidence is now accumulating that the serotonergic nervous system is involved in the pathology of anxiety and can provide benefits in the treatment of related disorders through its diverse functions, notably the modulation of stress, fear and memory. Among serotonin receptor subtypes, the 5-HT2A receptor arouses great interest. This receptor displays original pharmacological properties i.e., cooperation with β-arrestins and homo−/hetero-dimerization regulating its intracellular signaling and its ability to control the serotonergic system. The present chapter provides insight into the mechanisms by which the 5-HT2A receptor may alter the activity of 5-HT neurons but also of the brain regions receiving a dense serotonergic innervation (i.e, the amygdala, the hippocampus and the prefrontal cortex). An overview of the literature is proposed to recapitulate the pharmacological and genetic studies in patients or relevant animal models supporting a role of the 5-HT2A receptor on various forms of anxiety. Moreover, we envision the future directions that we might follow to develop new anxiolytic strategies based on the manipulation of 5-HT2A-mediated signaling. Doing so, we also point some inconsistencies illustrating the difficulty to target this receptor as a valid alternative to benzodiazepines.

Keywords

5-HT2A receptor Amygdala Animal studies Anxiety Fear memory Hippocampus Monoaminergic circuits 

Abbreviations

5-HT

Serotonin

5-HT2A

5-Hydroxytryptamine 2A

AMY

Amygdala

BDNF

Brain-derived neurotrophic factor

BLA

Basolateral complex of amygdala

CeA

Central nucleus of amygdala

CRF

Corticotropin releasing factor

CRFR

Corticotropin releasing factor receptor

DA

Dopamine

DAG

Diacylglycerol

DCX

Doublecortin

DG

Dentate gyrus

DR

Dorsal raphe

EPM

Elevated plus maze

ERK

Extracellular signal-regulated kinase

ETM

Elevated T-maze

FPT

Four plate test

GAD

Generalized anxiety disorders

GC

Granule cell

GDNF

Glial cell line-derived neurotrophic factor

HP

Hippocampus

IP3

Inositol Triphosphate

IPSCs

Inhibitory post-synaptic currents

LC

Locus coeruleus

LSD

Lysergic acid diethylamide

MeA

Medial amygdala

mPFCx

Medial prefrontal cortex

MR

Median raphe

NE

Norepinephrine

NSF

Novelty suppressed feeding

OF

Open field

OIC

Object in Context Recognition Task

PAG

Periaqueducal grey

PD

Panic disorders

PKC

Protein kinase C

PLC

Phospholipase C

PV

Parvalbumin

SAD

Social anxiety disorder

SGZ

Subgranular zone

SNOR

Spontaneous Novel Object Recognition task

SNP

Single nucleotide polymorphism

SOM

Somatostatin

SSRIs

Serotonin selective reuptake inhibitors

TI

Tonic immobility

TMOR

Temporal Order Recognition Task

Tph

Tryptophan hydroxylase

VEGF

Vascular endothelial growth factor

VTA

Ventral tegmental area

References

  1. 1.
    Bombardi C (2012) Neuronal localization of 5-HT2A receptor immunoreactivity in the rat hippocampal region. Brain Res Bull 87:259–273PubMedCrossRefGoogle Scholar
  2. 2.
    Bombardi C (2014) Neuronal localization of the 5-HT2 receptor family in the amygdaloid complex. Front Pharmacol 5:68PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Kroll T, Elmenhorst D, Matusch A, Celik AA, Wedekind F, Weisshaupt A, Beer S, Bauer A (2014) [(1)(8)F]Altanserin and small animal PET: impact of multidrug efflux transporters on ligand brain uptake and subsequent quantification of 5-HT(2)A receptor densities in the rat brain. Nucl Med Biol 41:1–9PubMedCrossRefGoogle Scholar
  4. 4.
    Quesseveur G, Nguyen HT, Gardier AM, Guiard BP (2012) 5-HT2 ligands in the treatment of anxiety and depression. Expert Opin Investig Drugs 21:1701–1725PubMedCrossRefGoogle Scholar
  5. 5.
    Roth BL (2011) Irving Page Lecture: 5-HT(2A) serotonin receptor biology: interacting proteins, kinases and paradoxical regulation. Neuropharmacology 61:348–354PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Abbas A, Roth BL (2008) Arresting serotonin. Proc Natl Acad Sci U S A 105:831–832PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Guiard BP, Di Giovanni G (2015) Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link? Front Pharmacol 6:46PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Schmid CL, Raehal KM, Bohn LM (2008) Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo. Proc Natl Acad Sci U S A 105:1079–1084PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Raote I, Bhattacharya A, Panicker MM (2007) Serotonin 2A (5-HT2A) receptor function: ligand-dependent mechanisms and pathways. CRC, Boca Raton, FLGoogle Scholar
  10. 10.
    Brea J, Castro M, Giraldo J, Lopez-Gimenez JF, Padin JF, Quintian F, Cadavid MI, Vilaro MT, Mengod G, Berg KA, Clarke WP, Vilardaga JP, Milligan G, Loza MI (2009) Evidence for distinct antagonist-revealed functional states of 5-hydroxytryptamine(2A) receptor homodimers. Mol Pharmacol 75:1380–1391PubMedCrossRefGoogle Scholar
  11. 11.
    Delille HK, Becker JM, Burkhardt S, Bleher B, Terstappen GC, Schmidt M, Meyer AH, Unger L, Marek GJ, Mezler M (2012) Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology 62:2184–2191PubMedCrossRefGoogle Scholar
  12. 12.
    Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452:93–97PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzalez-Maeso J (2011) Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett 493:76–79PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Hanks JB, Gonzalez-Maeso J (2013) Animal models of serotonergic psychedelics. ACS Chem Neurosci 4:33–42PubMedCrossRefGoogle Scholar
  15. 15.
    Lowry CA, Johnson PL, Hay-Schmidt A, Mikkelsen J, Shekhar A (2005) Modulation of anxiety circuits by serotonergic systems. Stress 8:233–246PubMedCrossRefGoogle Scholar
  16. 16.
    Dean B, Tawadros N, Seo MS, Jeon WJ, Everall I, Scarr E, Gibbons A (2014) Lower cortical serotonin 2A receptors in major depressive disorder, suicide and in rats after administration of imipramine. Int J Neuropsychopharmacol 17:895–906PubMedCrossRefGoogle Scholar
  17. 17.
    Massou JM, Trichard C, Attar-Levy D, Feline A, Corruble E, Beaufils B, Martinot JL (1997) Frontal 5-HT2A receptors studied in depressive patients during chronic treatment by selective serotonin reuptake inhibitors. Psychopharmacology 133:99–101PubMedCrossRefGoogle Scholar
  18. 18.
    Muguruza C, Miranda-Azpiazu P, Diez-Alarcia R, Morentin B, Gonzalez-Maeso J, Callado LF, Meana JJ (2014) Evaluation of 5-HT2A and mGlu2/3 receptors in postmortem prefrontal cortex of subjects with major depressive disorder: effect of antidepressant treatment. Neuropharmacology 86:311–318PubMedCrossRefGoogle Scholar
  19. 19.
    Zanardi R, Artigas F, Moresco R, Colombo C, Messa C, Gobbo C, Smeraldi E, Fazio F (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 21:53–58PubMedCrossRefGoogle Scholar
  20. 20.
    Messa C, Colombo C, Moresco RM, Gobbo C, Galli L, Lucignani G, Gilardi MC, Rizzo G, Smeraldi E, Zanardi R, Artigas F, Fazio F (2003) 5-HT(2A) receptor binding is reduced in drug-naive and unchanged in SSRI-responder depressed patients compared to healthy controls: a PET study. Psychopharmacology 167:72–78PubMedCrossRefGoogle Scholar
  21. 21.
    Bayliss DA, Li YW, Talley EM (1997) Effects of serotonin on caudal raphe neurons: activation of an inwardly rectifying potassium conductance. J Neurophysiol 77:1349–1361PubMedCrossRefGoogle Scholar
  22. 22.
    Pompeiano M, Palacios JM, Mengod G (1994) Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Brain Res Mol Brain Res 23:163–178PubMedCrossRefGoogle Scholar
  23. 23.
    Xie H, Ma F, Zhang YQ, Gao X, Wu GC (2002) Expression of 5-HT(2A) receptor mRNA in some nuclei of brain stem enhanced in monoarthritic rats. Brain Res 954:94–99PubMedCrossRefGoogle Scholar
  24. 24.
    Boothman LJ, Sharp T (2005) A role for midbrain raphe gamma aminobutyric acid neurons in 5-hydroxytryptamine feedback control. Neuroreport 16:891–896PubMedCrossRefGoogle Scholar
  25. 25.
    Boothman LJ, Allers KA, Rasmussen K, Sharp T (2003) 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 139:998–1004PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Bortolozzi A, Amargos-Bosch M, Adell A, Diaz-Mataix L, Serrats J, Pons S, Artigas F (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 18:1235–1246PubMedCrossRefGoogle Scholar
  27. 27.
    Garratt JC, Kidd EJ, Wright IK, Marsden CA (1991) Inhibition of 5-hydroxytryptamine neuronal activity by the 5-HT agonist, DOI. Eur J Pharmacol 199:349–355PubMedCrossRefGoogle Scholar
  28. 28.
    Martin-Ruiz R, Puig MV, Celada P, Shapiro DA, Roth BL, Mengod G, Artigas F (2001) Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci 21:9856–9866PubMedGoogle Scholar
  29. 29.
    Quesseveur G, Reperant C, David DJ, Gardier AM, Sanchez C, Guiard BP (2013a) 5-HT(2)A receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system. Exp Brain Res 226:285–295PubMedCrossRefGoogle Scholar
  30. 30.
    Wright IK, Garratt JC, Marsden CA (1990) Effects of a selective 5-HT2 agonist, DOI, on 5-HT neuronal firing in the dorsal raphe nucleus and 5-HT release and metabolism in the frontal cortex. Br J Pharmacol 99:221–222PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Guiard BP, El Mansari M, Blier P (2009) Prospect of a dopamine contribution in the next generation of antidepressant drugs: the triple reuptake inhibitors. Curr Drug Targets 10:1069–1084PubMedCrossRefGoogle Scholar
  32. 32.
    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 11:625–639PubMedCrossRefGoogle Scholar
  33. 33.
    Szabo ST, Blier P (2001) Functional and pharmacological characterization of the modulatory role of serotonin on the firing activity of locus coeruleus norepinephrine neurons. Brain Res 922:9–20PubMedCrossRefGoogle Scholar
  34. 34.
    Szabo ST, de Montigny C, Blier P (1999) Modulation of noradrenergic neuronal firing by selective serotonin reuptake blockers. Br J Pharmacol 126:568–571PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Aman TK, Shen RY, Haj-Dahmane S (2007) D2-like dopamine receptors depolarize dorsal raphe serotonin neurons through the activation of nonselective cationic conductance. J Pharmacol Exp Ther 320:376–385PubMedCrossRefGoogle Scholar
  36. 36.
    Haj-Dahmane S (2001) D2-like dopamine receptor activation excites rat dorsal raphe 5-HT neurons in vitro. Eur J Neurosci 14:125–134PubMedCrossRefGoogle Scholar
  37. 37.
    Dziedzicka-Wasylewska M, Faron-Gorecka A, Gorecki A, Kusemider M (2008) Mechanism of action of clozapine in the context of dopamine D1-D2 receptor hetero-dimerization--a working hypothesis. Pharmacol Rep 60:581–587PubMedGoogle Scholar
  38. 38.
    Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci 21:9917–9929PubMedGoogle Scholar
  39. 39.
    Puig MV, Celada P, Diaz-Mataix L, Artigas F (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 13:870–882PubMedCrossRefGoogle Scholar
  40. 40.
    Vazquez-Borsetti P, Celada P, Cortes R, Artigas F (2011) Simultaneous projections from prefrontal cortex to dopaminergic and serotonergic nuclei. Int J Neuropsychopharmacol 14:289–302PubMedCrossRefGoogle Scholar
  41. 41.
    Bortolozzi A, Diaz-Mataix L, Scorza MC, Celada P, Artigas F (2005) The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem 95:1597–1607PubMedCrossRefGoogle Scholar
  42. 42.
    Celada P, Puig MV, Artigas F (2013) Serotonin modulation of cortical neurons and networks. Front Integr Neurosci 7:25PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Asan E, Steinke M, Lesch KP (2013) Serotonergic innervation of the amygdala: targets, receptors, and implications for stress and anxiety. Histochem Cell Biol 139:785–813PubMedCrossRefGoogle Scholar
  44. 44.
    Inoue T, Koyama T, Yamashita I (1993) Effect of conditioned fear stress on serotonin metabolism in the rat brain. Pharmacol Biochem Behav 44:371–374PubMedCrossRefGoogle Scholar
  45. 45.
    Mo B, Feng N, Renner K, Forster G (2008) Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors. Brain Res Bull 76:493–498PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Spannuth BM, Hale MW, Evans AK, Lukkes JL, Campeau S, Lowry CA (2011) Investigation of a central nucleus of the amygdala/dorsal raphe nucleus serotonergic circuit implicated in fear-potentiated startle. Neuroscience 179:104–119PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Baratta MV, Kodandaramaiah SB, Monahan PE, Yao J, Weber MD, Lin PA, Gisabella B, Petrossian N, Amat J, Kim K, Yang A, Forest CR, Boyden ES, Goosens KA (2016) Stress enables reinforcement-elicited serotonergic consolidation of fear memory. Biol Psychiatry 79:814–822PubMedCrossRefGoogle Scholar
  48. 48.
    Christianson JP, Ragole T, Amat J, Greenwood BN, Strong PV, Paul ED, Fleshner M, Watkins LR, Maier SF (2010) 5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry 67:339–345PubMedCrossRefGoogle Scholar
  49. 49.
    Johnson PL, Molosh A, Fitz SD, Arendt D, Deehan GA, Federici LM, Bernabe C, Engleman EA, Rodd ZA, Lowry CA, Shekhar A (2015) Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning. Pharmacol Biochem Behav 138:174–179PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Hamon M (1994) Neuropharmacology of anxiety: perspectives and prospects. Trends Pharmacol Sci 15:36–39PubMedCrossRefGoogle Scholar
  51. 51.
    Matsuzaki I, Takamatsu Y, Moroji T (1989) The effects of intracerebroventricularly injected corticotropin-releasing factor (CRF) on the central nervous system: behavioural and biochemical studies. Neuropeptides 13:147–155PubMedCrossRefGoogle Scholar
  52. 52.
    Day HE, Greenwood BN, Hammack SE, Watkins LR, Fleshner M, Maier SF, Campeau S (2004) Differential expression of 5HT-1A, alpha 1b adrenergic, CRF-R1, and CRF-R2 receptor mRNA in serotonergic, gamma-aminobutyric acidergic, and catecholaminergic cells of the rat dorsal raphe nucleus. J Comp Neurol 474:364–378PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Pringle RB, Mouw NJ, Lukkes JL, Forster GL (2008) Amphetamine treatment increases corticotropin-releasing factor receptors in the dorsal raphe nucleus. Neurosci Res 62:62–65PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Amat J, Tamblyn JP, Paul ED, Bland ST, Amat P, Foster AC, Watkins LR, Maier SF (2004) Microinjection of urocortin 2 into the dorsal raphe nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala. Neuroscience 129:509–519PubMedCrossRefGoogle Scholar
  55. 55.
    Pernar L, Curtis AL, Vale WW, Rivier JE, Valentino RJ (2004) Selective activation of corticotropin-releasing factor-2 receptors on neurochemically identified neurons in the rat dorsal raphe nucleus reveals dual actions. J Neurosci 24:1305–1311PubMedCrossRefGoogle Scholar
  56. 56.
    Scholl JL, Vuong SM, Forster GL (2010) Chronic amphetamine treatment enhances corticotropin-releasing factor-induced serotonin release in the amygdala. Eur J Pharmacol 644:80–87PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Lukkes J, Vuong S, Scholl J, Oliver H, Forster G (2009) Corticotropin-releasing factor receptor antagonism within the dorsal raphe nucleus reduces social anxiety-like behavior after early-life social isolation. J Neurosci 29:9955–9960PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Bledsoe AC, Oliver KM, Scholl JL, Forster GL (2011) Anxiety states induced by post-weaning social isolation are mediated by CRF receptors in the dorsal raphe nucleus. Brain Res Bull 85:117–122PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Bombardi C (2011) Distribution of 5-HT2A receptor immunoreactivity in the rat amygdaloid complex and colocalization with gamma-aminobutyric acid. Brain Res 1370:112–128PubMedCrossRefGoogle Scholar
  60. 60.
    Hale MW, Johnson PL, Westerman AM, Abrams JK, Shekhar A, Lowry CA (2010) Multiple anxiogenic drugs recruit a parvalbumin-containing subpopulation of GABAergic interneurons in the basolateral amygdala. Prog Neuro-Psychopharmacol Biol Psychiatry 34:1285–1293CrossRefGoogle Scholar
  61. 61.
    McDonald AJ, Mascagni F (2007) Neuronal localization of 5-HT type 2A receptor immunoreactivity in the rat basolateral amygdala. Neuroscience 146:306–320PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Hale MW, Bouwknecht JA, Spiga F, Shekhar A, Lowry CA (2006) Exposure to high- and low-light conditions in an open-field test of anxiety increases c-Fos expression in specific subdivisions of the rat basolateral amygdaloid complex. Brain Res Bull 71:174–182PubMedCrossRefGoogle Scholar
  63. 63.
    Hale MW, Hay-Schmidt A, Mikkelsen JD, Poulsen B, Bouwknecht JA, Evans AK, Stamper CE, Shekhar A, Lowry CA (2008a) Exposure to an open-field arena increases c-Fos expression in a subpopulation of neurons in the dorsal raphe nucleus, including neurons projecting to the basolateral amygdaloid complex. Neuroscience 157:733–748PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Hale MW, Hay-Schmidt A, Mikkelsen JD, Poulsen B, Shekhar A, Lowry CA (2008b) Exposure to an open-field arena increases c-Fos expression in a distributed anxiety-related system projecting to the basolateral amygdaloid complex. Neuroscience 155:659–672PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Bocchio M, Fucsina G, Oikonomidis L, McHugh SB, Bannerman DM, Sharp T, Capogna M (2015) Increased serotonin transporter expression reduces fear and recruitment of parvalbumin interneurons of the amygdala. Neuropsychopharmacology 40:3015–3026PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Jiang X, Xing G, Yang C, Verma A, Zhang L, Li H (2009) Stress impairs 5-HT2A receptor-mediated serotonergic facilitation of GABA release in juvenile rat basolateral amygdala. Neuropsychopharmacology 34:410–423PubMedCrossRefGoogle Scholar
  67. 67.
    Rainnie DG (1999) Serotonergic modulation of neurotransmission in the rat basolateral amygdala. J Neurophysiol 82:69–85PubMedCrossRefGoogle Scholar
  68. 68.
    Sengupta A, Bocchio M, Bannerman DM, Sharp T, Capogna M (2017) Control of amygdala circuits by 5-HT neurons via 5-HT and glutamate cotransmission. J Neurosci 37:1785–1796PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409:187–209PubMedCrossRefGoogle Scholar
  70. 70.
    Bombardi C, Di Giovanni G (2013) Functional anatomy of 5-HT2A receptors in the amygdala and hippocampal complex: relevance to memory functions. Exp Brain Res 230:427–439PubMedCrossRefGoogle Scholar
  71. 71.
    Miller BR, Hen R (2015) The current state of the neurogenic theory of depression and anxiety. Curr Opin Neurobiol 30:51–58PubMedCrossRefGoogle Scholar
  72. 72.
    Kheirbek MA, Drew LJ, Burghardt NS, Costantini DO, Tannenholz L, Ahmari SE, Zeng H, Fenton AA, Hen R (2013) Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron 77:955–968PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Samuels BA, Hen R (2011) Neurogenesis and affective disorders. Eur J Neurosci 33:1152–1159PubMedCrossRefGoogle Scholar
  74. 74.
    Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110PubMedGoogle Scholar
  75. 75.
    Brezun JM, Daszuta A (2000) Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur J Neurosci 12:391–396PubMedCrossRefGoogle Scholar
  76. 76.
    Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547PubMedGoogle Scholar
  77. 77.
    Sairanen M, Lucas G, Ernfors P, Castren M, Castren E (2005) Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25:1089–1094PubMedCrossRefGoogle Scholar
  78. 78.
    Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768–1777PubMedGoogle Scholar
  79. 79.
    Klempin F, Babu H, De Pietri Tonelli D, Alarcon E, Fabel K, Kempermann G (2010) Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci 3Google Scholar
  80. 80.
    Banasr M, Hery M, Printemps R, Daszuta A (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 29:450–460PubMedCrossRefGoogle Scholar
  81. 81.
    Jha S, Rajendran R, Fernandes KA, Vaidya VA (2008) 5-HT2A/2C receptor blockade regulates progenitor cell proliferation in the adult rat hippocampus. Neurosci Lett 441:210–214PubMedCrossRefGoogle Scholar
  82. 82.
    Vaidya VA, Marek GJ, Aghajanian GK, Duman RS (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 17:2785–2795PubMedGoogle Scholar
  83. 83.
    Freund TF, Gulyas AI, Acsady L, Gorcs T, Toth K (1990) Serotonergic control of the hippocampus via local inhibitory interneurons. Proc Natl Acad Sci U S A 87:8501–8505PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    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):629–639PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Peddie CJ, Davies HA, Colyer FM, Stewart MG, Rodriguez JJ (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 211:561–573PubMedCrossRefGoogle Scholar
  86. 86.
    Banasr M, Chowdhury GM, Terwilliger R, Newton SS, Duman RS, Behar KL, Sanacora G (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 15:501–511PubMedCrossRefGoogle Scholar
  87. 87.
    Quesseveur G, Gardier AM, Guiard BP (2013b) The monoaminergic tripartite synapse: a putative target for currently available antidepressant drugs. Curr Drug Targets 14:1277–1294PubMedCrossRefGoogle Scholar
  88. 88.
    Rajkowska G (2000) Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 48:766–777PubMedCrossRefGoogle Scholar
  89. 89.
    Czeh B, Simon M, Schmelting B, Hiemke C, Fuchs E (2006) Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology 31:1616–1626PubMedCrossRefGoogle Scholar
  90. 90.
    Hansson E, Simonsson P, Alling C (1987) 5-Hydroxytryptamine stimulates the formation of inositol phosphate in astrocytes from different regions of the brain. Neuropharmacology 26:1377–1382PubMedCrossRefGoogle Scholar
  91. 91.
    Hirst WD, Price GW, Rattray M, Wilkin GP (1997) Identification of 5-hydroxytryptamine receptors positively coupled to adenylyl cyclase in rat cultured astrocytes. Br J Pharmacol 120:509–515PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Zhang S, Li B, Lovatt D, Xu J, Song D, Goldman SA, Nedergaard M, Hertz L, Peng L (2010) 5-HT2B receptors are expressed on astrocytes from brain and in culture and are a chronic target for all five conventional ‘serotonin-specific reuptake inhibitors’. Neuron Glia Biol 6:113–125PubMedCrossRefGoogle Scholar
  93. 93.
    Li B, Zhang S, Li M, Hertz L, Peng L (2009) Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation. Psychopharmacology 207:1–12PubMedCrossRefGoogle Scholar
  94. 94.
    Musazzi L, Mallei A, Tardito D, Gruber SH, El Khoury A, Racagni G, Mathe AA, Popoli M (2010) Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression. J Psychiatr Res 44:511–520PubMedCrossRefGoogle Scholar
  95. 95.
    Qi X, Lin W, Li J, Li H, Wang W, Wang D, Sun M (2008) Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol Dis 31:278–285PubMedCrossRefGoogle Scholar
  96. 96.
    Morrens J, Van Den Broeck W, Kempermann G (2011) Glial cells in adult neurogenesis. GliaGoogle Scholar
  97. 97.
    Li B, Zhang S, Zhang H, Nu W, Cai L, Hertz L, Peng L (2008) Fluoxetine-mediated 5-HT2B receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation. Psychopharmacology 201:443–458PubMedCrossRefGoogle Scholar
  98. 98.
    Tsuchioka M, Takebayashi M, Hisaoka K, Maeda N, Nakata Y (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 106:244–257PubMedCrossRefGoogle Scholar
  99. 99.
    Meller R, Babity JM, Grahame-Smith DG (2002) 5-HT2A receptor activation leads to increased BDNF mRNA expression in C6 glioma cells. NeuroMolecular Med 1:197–205PubMedCrossRefGoogle Scholar
  100. 100.
    Quesseveur G, David DJ, Gaillard MC, Pla P, Wu MV, Nguyen HT, Nicolas V, Auregan G, David I, Dranovsky A, Hantraye P, Hen R, Gardier AM, Deglon N, Guiard BP (2013c) BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities. Transl Psychiatry 3:e253Google Scholar
  101. 101.
    Zhang G, Stackman RW (2015) The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 6:225Google Scholar
  102. 102.
    Xia Z, Gray JA, Compton-Toth BA, Roth BL (2003) A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction. J Biol Chem 278:21901–21908PubMedCrossRefGoogle Scholar
  103. 103.
    Arvanov VL, Liang X, Russo A, Wang RY (1999) LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex. Eur J Neurosci 11:3064–3072PubMedCrossRefGoogle 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 779:309–313PubMedCrossRefGoogle Scholar
  105. 105.
    Snigdha S, Horiguchi M, Huang M, Li Z, Shahid M, Neill JC, Meltzer HY (2010) Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 332:622–631PubMedCrossRefGoogle Scholar
  106. 106.
    Nemeroff CB (2002) Recent advances in the neurobiology of depression. Psychopharmacol Bull 36(Suppl 2):6–23PubMedGoogle Scholar
  107. 107.
    Griebel G, Perrault G, Sanger DJ (1997) A comparative study of the effects of selective and non-selective 5-HT2 receptor subtype antagonists in rat and mouse models of anxiety. Neuropharmacology 36:793–802PubMedCrossRefGoogle Scholar
  108. 108.
    Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PL, McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW, Widmaier C (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277:968–981PubMedGoogle Scholar
  109. 109.
    Setem J, Pinheiro AP, Motta VA, Morato S, Cruz AP (1999) Ethopharmacological analysis of 5-HT ligands on the rat elevated plus-maze. Pharmacol Biochem Behav 62:515–521PubMedCrossRefGoogle Scholar
  110. 110.
    Onaivi ES, Bishop-Robinson C, Darmani NA, Sanders-Bush E (1995) Behavioral effects of (+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (DOI) in the elevated plus-maze test. Life Sci 57:2455–2466PubMedCrossRefGoogle Scholar
  111. 111.
    Nic Dhonnchadha BA, Bourin M, Hascoet M (2003a) Anxiolytic-like effects of 5-HT2 ligands on three mouse models of anxiety. Behav Brain Res 140:203–214PubMedCrossRefGoogle Scholar
  112. 112.
    Nic Dhonnchadha BA, Hascoet M, Jolliet P, Bourin M (2003b) Evidence for a 5-HT2A receptor mode of action in the anxiolytic-like properties of DOI in mice. Behav Brain Res 147:175–184PubMedCrossRefGoogle Scholar
  113. 113.
    Masse F, Hascoet M, Dailly E, Bourin M (2006) Effect of noradrenergic system on the anxiolytic-like effect of DOI (5-HT2A/2C agonists) in the four-plate test. Psychopharmacology 183:471–481PubMedCrossRefGoogle Scholar
  114. 114.
    Clinard CT, Bader LR, Sullivan MA, Cooper MA (2015) Activation of 5-HT2a receptors in the basolateral amygdala promotes defeat-induced anxiety and the acquisition of conditioned defeat in Syrian hamsters. Neuropharmacology 90:102–112PubMedCrossRefGoogle Scholar
  115. 115.
    Cornelio AM, Nunes-de-Souza RL (2007) Anxiogenic-like effects of mCPP microinfusions into the amygdala (but not dorsal or ventral hippocampus) in mice exposed to elevated plus-maze. Behav Brain Res 178:82–89PubMedCrossRefGoogle Scholar
  116. 116.
    Leite-Panissi CR, Ferrarese AA, Terzian AL, Menescal-de-Oliveira L (2006) Serotoninergic activation of the basolateral amygdala and modulation of tonic immobility in guinea pig. Brain Res Bull 69:356–364PubMedCrossRefGoogle Scholar
  117. 117.
    Klemm WR (1971) Neurophysiologic studies of the immobility reflex (“animal hypnosis”). Neurosci Res (N Y) 4:165–212CrossRefGoogle Scholar
  118. 118.
    de Paula BB, Leite-Panissi CR (2016) Distinct effect of 5-HT1A and 5-HT2A receptors in the medial nucleus of the amygdala on tonic immobility behavior. Brain Res 1643:152–158PubMedCrossRefGoogle Scholar
  119. 119.
    Petit-Demouliere B, Masse F, Cogrel N, Hascoet M, Bourin M (2009) Brain structures implicated in the four-plate test in naive and experienced Swiss mice using injection of diazepam and the 5-HT2A agonist DOI. Behav Brain Res 204:200–205PubMedCrossRefGoogle Scholar
  120. 120.
    Gomes KS, Nunes-De-Souza RL (2009) Implication of the 5-HT2A and 5-HT2C (but not 5HT1A) receptors located within the periaqueductal gray in the elevated plus-maze test-retest paradigm in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 33:1261–1269CrossRefGoogle Scholar
  121. 121.
    Sarkar A, Chachra P, Vaidya VA (2014) Postnatal fluoxetine-evoked anxiety is prevented by concomitant 5-HT2A/C receptor blockade and mimicked by postnatal 5-HT2A/C receptor stimulation. Biol Psychiatry 76:858–868PubMedCrossRefGoogle Scholar
  122. 122.
    Ceulemans DL, Hoppenbrouwers ML, Gelders YG, Reyntjens AJ (1985) The influence of ritanserin, a serotonin antagonist, in anxiety disorders: a double-blind placebo-controlled study versus lorazepam. Pharmacopsychiatry 18:303–305PubMedCrossRefGoogle Scholar
  123. 123.
    Pigott TA, Zohar J, Hill JL, Bernstein SE, Grover GN, Zohar-Kadouch RC, Murphy DL (1991) Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder. Biol Psychiatry 29:418–426PubMedCrossRefGoogle Scholar
  124. 124.
    Bystritsky A, Rosen R, Suri R, Vapnik T (1999) Pilot open-label study of nefazodone in panic disorder. Depress Anxiety 10:137–139PubMedCrossRefGoogle Scholar
  125. 125.
    Ribeiro L, Busnello JV, Kauer-Sant'Anna M, Madruga M, Quevedo J, Busnello EA, Kapczinski F (2001) Mirtazapine versus fluoxetine in the treatment of panic disorder. Braz J Med Biol Res 34:1303–1307PubMedCrossRefGoogle Scholar
  126. 126.
    Blier P, Szabo ST (2005) Potential mechanisms of action of atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry 66(Suppl 8):30–40PubMedGoogle Scholar
  127. 127.
    Sramek JJ, Robinson RE, Suri A, Cutler NR (1995) Efficacy trial of the 5-HT2 antagonist MDL 11,939 in patients with generalized anxiety disorder. J Clin Psychopharmacol 15:20–22PubMedCrossRefGoogle Scholar
  128. 128.
    Pilkinton P, Berry C, Norrholm S, Bartolucci A, Birur B, Davis LL (2016) An open label pilot study of adjunctive asenapine for the treatment of posttraumatic stress disorder. Psychopharmacol Bull 46:8–17PubMedPubMedCentralGoogle Scholar
  129. 129.
    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 15:1219–1229PubMedCrossRefGoogle Scholar
  130. 130.
    Greig SL (2015) Brexpiprazole: First Global Approval. Drugs 75:1687–1697PubMedCrossRefGoogle Scholar
  131. 131.
    Llorca PM, Lancon C, Blanc O, de Chazeron I, Samalin L, Caci H, Lesturgeon JA, Bayle FJ (2014) A composite scale applied to evaluate anxiety in schizophrenic patients (SAES). Eur Arch Psychiatry Clin Neurosci 264:171–178PubMedCrossRefGoogle Scholar
  132. 132.
    Pallanti S, Cantisani A, Grassi G (2013) Anxiety as a core aspect of schizophrenia. Curr Psychiatry Rep 15:354PubMedCrossRefGoogle Scholar
  133. 133.
    Braga RJ, Reynolds GP, Siris SG (2013) Anxiety comorbidity in schizophrenia. Psychiatry Res 210:1–7PubMedCrossRefGoogle Scholar
  134. 134.
    Garay RP, Samalin L, Hameg A, Llorca PM (2015) Investigational drugs for anxiety in patients with schizophrenia. Expert Opin Investig Drugs 24:507–517PubMedCrossRefGoogle Scholar
  135. 135.
    Petit AC, Quesseveur G, Gressier F, Colle R, David DJ, Gardier AM, Ferreri F, Lepine JP, Falissard B, Verstuyft C, Guiard BP, Corruble E (2014) Converging translational evidence for the involvement of the serotonin 2A receptor gene in major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 54:76–82CrossRefGoogle Scholar
  136. 136.
    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 105:142–153PubMedCrossRefGoogle Scholar
  137. 137.
    Weisstaub NV, Zhou M, Lira A, Lambe E, Gonzalez-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 313:536–540PubMedCrossRefGoogle Scholar
  138. 138.
    Bandelow B (2008) The medical treatment of obsessive-compulsive disorder and anxiety. CNS Spectr 13:37–46PubMedCrossRefGoogle Scholar
  139. 139.
    Lemonde S, Du L, Bakish D, Hrdina P, Albert PR (2004) Association of the C(−1019)G 5-HT1A functional promoter polymorphism with antidepressant response. Int J Neuropsychopharmacol 7:501–506PubMedCrossRefGoogle Scholar
  140. 140.
    Richardson-Jones JW, Craige CP, Guiard BP, Stephen A, Metzger KL, Kung HF, Gardier AM, Dranovsky A, David DJ, Beck SG, Hen R, Leonardo ED (2010) 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65:40–52PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Bondy B, Spaeth M, Offenbaecher M, Glatzeder K, Stratz T, Schwarz M, de Jonge S, Kruger M, Engel RR, Farber L, Pongratz DE, Ackenheil M (1999) The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia. Neurobiol Dis 6:433–439PubMedCrossRefGoogle Scholar
  142. 142.
    Arranz MJ, Munro J, Owen MJ, Spurlock G, Sham PC, Zhao J, Kirov G, Collier DA, Kerwin RW (1998) Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry 3:61–66PubMedCrossRefGoogle Scholar
  143. 143.
    Enoch MA, Kaye WH, Rotondo A, Greenberg BD, Murphy DL, Goldman D (1998) 5-HT2A promoter polymorphism -1438G/A, anorexia nervosa, and obsessive-compulsive disorder. Lancet 351:1785–1786PubMedCrossRefGoogle Scholar
  144. 144.
    Walitza S, Wewetzer C, Warnke A, Gerlach M, Geller F, Gerber G, Gorg T, Herpertz-Dahlmann B, Schulz E, Remschmidt H, Hebebrand J, Hinney A (2002) 5-HT2A promoter polymorphism -1438G/A in children and adolescents with obsessive-compulsive disorders. Mol Psychiatry 7:1054–1057PubMedCrossRefGoogle Scholar
  145. 145.
    D’Avanzato C, Dalrymple KL (2016) Recent insight into the subtypes of social anxiety disorder. Curr Psychiatry Rep 18:50PubMedCrossRefGoogle Scholar
  146. 146.
    Lochner C, Hemmings S, Seedat S, Kinnear C, Schoeman R, Annerbrink K, Olsson M, Eriksson E, Moolman-Smook J, Allgulander C, Stein DJ (2007) Genetics and personality traits in patients with social anxiety disorder: a case-control study in South Africa. Eur Neuropsychopharmacol 17:321–327PubMedCrossRefGoogle Scholar
  147. 147.
    Khait VD, Huang YY, Zalsman G, Oquendo MA, Brent DA, Harkavy-Friedman JM, Mann JJ (2005) Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects. Neuropsychopharmacology 30:166–172PubMedCrossRefGoogle Scholar
  148. 148.
    Polesskaya OO, Sokolov BP (2002) Differential expression of the “C” and “T” alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res 67:812–822PubMedCrossRefGoogle Scholar
  149. 149.
    Kogan CS, Stein DJ, Maj M, First MB, Emmelkamp PM, Reed GM (2016) The classification of anxiety and fear-related disorders in the ICD-11. Depress Anxiety 33:1141–1154PubMedCrossRefGoogle Scholar
  150. 150.
    Yoon HK, Yang JC, Lee HJ, Kim YK (2008) The association between serotonin-related gene polymorphisms and panic disorder. J Anxiety Disord 22:1529–1534PubMedCrossRefGoogle Scholar
  151. 151.
    Inada Y, Yoneda H, Koh J, Sakai J, Himei A, Kinoshita Y, Akabame K, Hiraoka Y, Sakai T (2003) Positive association between panic disorder and polymorphism of the serotonin 2A receptor gene. Psychiatry Res 118:25–31PubMedCrossRefGoogle Scholar
  152. 152.
    Martinez-Barrondo S, Saiz PA, Morales B, Garcia-Portilla MP, Coto E, Alvarez V, Bobes J (2005) Serotonin gene polymorphisms in patients with panic disorder. Actas Esp Psiquiatr 33:210–215PubMedGoogle Scholar
  153. 153.
    Rothe C, Koszycki D, Bradwejn J, King N, De Luca V, Shaikh S, Franke P, Garritsen H, Fritze J, Deckert J, Kennedy JL (2004) Association study of serotonin-2A receptor gene polymorphism and panic disorder in patients from Canada and Germany. Neurosci Lett 363:276–279PubMedCrossRefGoogle Scholar
  154. 154.
    Pollack MH (2005) Comorbid anxiety and depression. J Clin Psychiatry 66(Suppl 8):22–29PubMedGoogle Scholar
  155. 155.
    Arias B, Gasto C, Catalan R, Gutierrez B, Pintor L, Fananas L (2001) The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients. Am J Med Genet 105:801–804PubMedCrossRefGoogle Scholar
  156. 156.
    Du L, Bakish D, Lapierre YD, Ravindran AV, Hrdina PD (2000) Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder. Am J Med Genet 96:56–60PubMedCrossRefGoogle Scholar
  157. 157.
    Zhang HY, Ishigaki T, Tani K, Chen K, Shih JC, Miyasato K, Ohara K (1997) Serotonin2A receptor gene polymorphism in mood disorders. Biol Psychiatry 41:768–773PubMedCrossRefGoogle Scholar
  158. 158.
    Illi A, Setala-Soikkeli E, Viikki M, Poutanen O, Huhtala H, Mononen N, Lehtimaki T, Leinonen E, Kampman O (2009) 5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression. Neuroreport 20:1125–1128PubMedGoogle Scholar
  159. 159.
    Kishi T, Kitajima T, Tsunoka T, Ikeda M, Yamanouchi Y, Kinoshita Y, Kawashima K, Okochi T, Okumura T, Inada T, Ozaki N, Iwata N (2009) Genetic association analysis of serotonin 2A receptor gene (HTR2A) with bipolar disorder and major depressive disorder in the Japanese population. Neurosci Res 64:231–234PubMedCrossRefGoogle Scholar
  160. 160.
    Minov C, Baghai TC, Schule C, Zwanzger P, Schwarz MJ, Zill P, Rupprecht R, Bondy B (2001) Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neurosci Lett 303:119–122PubMedCrossRefGoogle Scholar
  161. 161.
    Christiansen L, Tan Q, Iachina M, Bathum L, Kruse TA, McGue M, Christensen K (2007) Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomatology in an elderly population. Biol Psychiatry 61:223–230PubMedCrossRefGoogle Scholar
  162. 162.
    Kamata M, Suzuki A, Yoshida K, Takahashi H, Higuchi H, Otani K (2011) Genetic polymorphisms in the serotonergic system and symptom clusters of major depressive disorder. J Affect Disord 135:374–376PubMedCrossRefGoogle Scholar
  163. 163.
    Tencomnao T, Thongrakard V, Phuchana W, Sritharathikhun T, Suttirat S (2010) No relationship found between -1438A/G polymorphism of the serotonin 2A receptor gene (rs6311) and major depression susceptibility in a northeastern Thai population. Genet Mol Res 9:1171–1176PubMedCrossRefGoogle Scholar
  164. 164.
    McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJ, Papanicolaou GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H (2006) Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 78:804–814PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Fabbri C, Souery D, Calati R, Crisafulli C, Chierchia A, Albani D, Forloni G, Chiesa A, Martines R, Sentissi O, Mendlewicz J, De Girolamo G, Serretti A (2015) Genetics of psychotropic medication induced side effects in two independent samples of bipolar patients. J Neural Transm (Vienna) 122:43–58CrossRefGoogle Scholar
  166. 166.
    Horstmann S, Lucae S, Menke A, Hennings JM, Ising M, Roeske D, Muller-Myhsok B, Holsboer F, Binder EB (2010) Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology 35:727–740PubMedCrossRefGoogle Scholar
  167. 167.
    Kato M, Zanardi R, Rossini D, De Ronchi D, Okugawa G, Kinoshita T, Colombo C, Serretti A (2009) 5-HT2A gene variants influence specific and different aspects of antidepressant response in Japanese and Italian mood disorder patients. Psychiatry Res 167:97–105PubMedCrossRefGoogle Scholar
  168. 168.
    Kishi T, Yoshimura R, Kitajima T, Okochi T, Okumura T, Tsunoka T, Yamanouchi Y, Kinoshita Y, Kawashima K, Naitoh H, Nakamura J, Ozaki N, Iwata N (2010) HTR2A is associated with SSRI response in major depressive disorder in a japanese cohort. NeuroMolecular Med 12:237–242PubMedCrossRefGoogle Scholar
  169. 169.
    Noro M, Antonijevic I, Forray C, Kasper S, Kocabas NA, Lecrubier Y, Linotte S, Mendlewicz J, Montgomery S, Snyder L, Souery D, Verbanck P, Zohar J, Massat I (2010) 5HT1A and 5HT2A receptor genes in treatment response phenotypes in major depressive disorder. Int Clin Psychopharmacol 25:228–231PubMedCrossRefGoogle Scholar
  170. 170.
    Viikki M, Huuhka K, Leinonen E, Illi A, Setala-Soikkeli E, Huuhka M, Mononen N, Lehtimaki T, Kampman O (2011) Interaction between two HTR2A polymorphisms and gender is associated with treatment response in MDD. Neurosci Lett 501:20–24PubMedCrossRefGoogle Scholar
  171. 171.
    Wilkie MJ, Smith G, Day RK, Matthews K, Smith D, Blackwood D, Reid IC, Wolf CR (2009) Polymorphisms in the SLC6A4 and HTR2A genes influence treatment outcome following antidepressant therapy. Pharmacogenomics J 9:61–70PubMedCrossRefGoogle Scholar
  172. 172.
    Meltzer CC, Smith G, DeKosky ST, Pollock BG, Mathis CA, Moore RY, Kupfer DJ, Reynolds CF III (1998a) Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology 18:407–430PubMedCrossRefGoogle Scholar
  173. 173.
    Marner L, Frokjaer VG, Kalbitzer J, Lehel S, Madsen K, Baare WF, Knudsen GM, Hasselbalch SG (2012) Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease: a combined [11C]DASB and [18F]altanserin-PET study. Neurobiol Aging 33:479–487PubMedCrossRefGoogle Scholar
  174. 174.
    Meltzer CC, Smith G, Price JC, Reynolds CF III, Mathis CA, Greer P, Lopresti B, Mintun MA, Pollock BG, Ben-Eliezer D, Cantwell MN, Kaye W, DeKosky ST (1998b) Reduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction. Brain Res 813:167–171PubMedCrossRefGoogle Scholar
  175. 175.
    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 6:298PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Zhang G, Asgeirsdottir HN, Cohen SJ, Munchow AH, Barrera MP, Stackman RW Jr (2013) Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology 64:403–413PubMedCrossRefGoogle Scholar
  177. 177.
    Bekinschtein P, Renner MC, Gonzalez MC, Weisstaub N (2013) Role of medial prefrontal cortex serotonin 2A receptors in the control of retrieval of recognition memory in rats. J Neurosci 33:15716–15725PubMedCrossRefGoogle Scholar
  178. 178.
    Quirk GJ, Pare D, Richardson R, Herry C, Monfils MH, Schiller D, Vicentic A (2010) Erasing fear memories with extinction training. J Neurosci 30:14993–14997PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Schmidt SD, Furini CR, Zinn CG, Cavalcante LE, Ferreira FF, Behling JA, Myskiw JC, Izquierdo I (2016) Modulation of the consolidation and reconsolidation of fear memory by three different serotonin receptors in hippocampus. Neurobiol Learn Mem 142:48–54Google Scholar
  180. 180.
    Pecknold JC (1993) Survey of the adjuvant use of benzodiazepines for treating outpatients with schizophrenia. J Psychiatry Neurosci 18:82–84PubMedPubMedCentralGoogle Scholar
  181. 181.
    Stein DJ, Miczek KA, Lucion AB, de Almeida RM (2013) Aggression-reducing effects of F15599, a novel selective 5-HT1A receptor agonist, after microinjection into the ventral orbital prefrontal cortex, but not in infralimbic cortex in male mice. Psychopharmacology 230:375–387PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Llado-Pelfort L, Assie MB, Newman-Tancredi A, Artigas F, Celada P (2010) Preferential in vivo action of F15599, a novel 5-HT(1A) receptor agonist, at postsynaptic 5-HT(1A) receptors. Br J Pharmacol 160:1929–1940PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Research Center on Animal Cognition, Center for Integrative BiologyUniversité Paul Sabatier, UMR 5169 CNRSToulouse Cedex 9France
  2. 2.Faculté de Pharmacie, Université Paris SudUniversité Paris-SaclayChatenay-MalabryFrance
  3. 3.Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI)Université de Toulouse; CNRS, UPSToulouseFrance

Personalised recommendations