Crosstalk Between 5-HT2A and mGlu2 Receptors: Implications in Schizophrenia and Its Treatment

  • José L. Moreno
  • Javier González-Maeso
Part of the The Receptors book series (REC, volume 32)


Schizophrenia is a psychiatric disorder that affects 1% of the population worldwide. The serotonin and glutamate receptor systems have been implicated in schizophrenia and its treatment. Serotonin 5-HT2A receptor is target of hallucinogens such as lysergic acid diethylamide (LSD) and psilocin, as well as involved in the mechanism of action of atypical antipsychotic drugs such as clozapine and risperidone. The metabotropic glutamate 2 (mGlu2) receptor modulates the physiological responses induced by the 5-HT2A receptor, and preclinical and clinical work suggests that this glutamate receptor may represent a new approach to treat schizophrenia. Here we review recent advances in our understanding of the crosstalk between these two receptors, as well as their implication in schizophrenia and antipsychotic drug action.


G protein-coupled receptor (GPCR) Serotonin 5-HT2A receptor Glutamate Metabotropic glutamate 2 receptor mGlu2 Schizophrenia Psychosis Antipsychotic Clozapine Lysergic acid diethylamide (LSD) GPCR dimer GPCR heterocomplex 


  1. 1.
    Adam D (2013) On the spectrum. Nature 496:416–418PubMedCrossRefGoogle Scholar
  2. 2.
    Lewis DA, Gonzalez-Burgos G (2006) Pathophysiologically based treatment interventions in schizophrenia. Nat Med 12:1016–1022PubMedCrossRefGoogle Scholar
  3. 3.
    van Os J, Kapur S (2009) Schizophrenia. Lancet 374:635–645PubMedCrossRefGoogle Scholar
  4. 4.
    Sawa A, Snyder SH (2002) Schizophrenia: diverse approaches to a complex disease. Science 296:692–695PubMedCrossRefGoogle Scholar
  5. 5.
    Freedman R (2003) Schizophrenia. N Engl J Med 349:1738–1749PubMedCrossRefGoogle Scholar
  6. 6.
    Lehmann HE, Hanrahan GE (1954) Chlorpromazine; new inhibiting agent for psychomotor excitement and manic states. AMA Arch Neurol Psychiatry 71:227–237PubMedCrossRefGoogle Scholar
  7. 7.
    Granger B, Albu S (2005) The haloperidol story. Ann Clin Psychiatry 17:137–140PubMedCrossRefGoogle Scholar
  8. 8.
    Hippius H (1999) A historical perspective of clozapine. J Clin Psychiatry 60(Suppl 12):22–23PubMedGoogle Scholar
  9. 9.
    Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA (2012) Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 17:1206–1227PubMedCrossRefGoogle Scholar
  10. 10.
    Meltzer HY (2013) Update on typical and atypical antipsychotic drugs. Annu Rev Med 64:393–406PubMedCrossRefGoogle Scholar
  11. 11.
    Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS, Li XM, Mahadik SP, Duman RS, Porter JH, Modica-Napolitano JS, Newton SS, Csernansky JG (2008) Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 60:358–403PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Ibrahim HM, Tamminga CA (2011) Schizophrenia: treatment targets beyond monoamine systems. Annu Rev Pharmacol Toxicol 51:189–209PubMedCrossRefGoogle Scholar
  13. 13.
    Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223PubMedCrossRefGoogle Scholar
  14. 14.
    Turlejski K (1996) Evolutionary ancient roles of serotonin: long-lasting regulation of activity and development. Acta Neurobiol Exp (Wars) 56:619–636Google Scholar
  15. 15.
    Janeway T, Richarson H, Park E (1918) Experiments on the vasoconstrictor action of blood serum. Arch Intern Med 21:565–571CrossRefGoogle Scholar
  16. 16.
    Reid G, Bick M (1942) Pharmacologically active substances in serum. Aust J Exp Biol Med Sci 20:33–46CrossRefGoogle Scholar
  17. 17.
    Zucker M (1944) A study of the substances in blood serum and platelets which stimulate smooth muscle. Am J Physiol 142:12–26Google Scholar
  18. 18.
    Erspamer V, Asero B (1952) Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 169:800–801PubMedCrossRefGoogle Scholar
  19. 19.
    Rapport MM, Green AA, Page IH (1947) Purification of the substance which is responsible for the vasoconstrictor activity of serum. Fed Proc 6:184PubMedGoogle Scholar
  20. 20.
    Rapport MM, Green AA, Page IH (1948) Serum vasoconstrictor, serotonin; isolation and characterization. J Biol Chem 176:1243–1251PubMedGoogle Scholar
  21. 21.
    Rapport MM, Green AA, Page IH (1948) Partial purification of the vasoconstrictor in beef serum. J Biol Chem 174:735–741PubMedGoogle Scholar
  22. 22.
    Rapport MM, Green AA, Page IH (1948) Crystalline serotonin. Science 108:329–330PubMedCrossRefGoogle Scholar
  23. 23.
    Reid G, Rand M (1952) Pharmacological actions of synthetic 5-hydroxytryptamine (serotonin, thrombocytin). Nature 169:801–802PubMedCrossRefGoogle Scholar
  24. 24.
    Mohammad-Zadeh LF, Moses L, Gwaltney-Brant SM (2008) Serotonin: a review. J Vet Pharmacol Ther 31:187–199PubMedCrossRefGoogle Scholar
  25. 25.
    Hofmann A (1979) How LSD originated. J Psychedelic Drugs 11:53–60PubMedCrossRefGoogle Scholar
  26. 26.
    Hofmann A (1980) LSD: my problem child. McGraw-Hill, New YorkGoogle Scholar
  27. 27.
    Aghajanian GK, Foote WE, Sheard MH (1968) Lysergic acid diethylamide: sensitive neuronal units in the midbrain raphe. Science 161:706–708PubMedCrossRefGoogle Scholar
  28. 28.
    Bennett JP Jr, Snyder SH (1976) Serotonin and lysergic acid diethylamide binding in rat brain membranes: relationship to postsynaptic serotonin receptors. Mol Pharmacol 12:373–389PubMedGoogle Scholar
  29. 29.
    Peroutka SJ, Lebovitz RM, Snyder SH (1979) Serotonin receptor binding sites affected differentially by guanine nucleotides. Mol Pharmacol 16:700–708PubMedGoogle Scholar
  30. 30.
    Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol. Mol Pharmacol 16:687–699PubMedGoogle Scholar
  31. 31.
    Kobilka BK, Frielle T, Collins S, Yang-Feng T, Kobilka TS, Francke U, Lefkowitz RJ, Caron MG (1987) An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins. Nature 329:75–79PubMedCrossRefGoogle Scholar
  32. 32.
    Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedCrossRefGoogle Scholar
  33. 33.
    Nichols DE, Nichols CD (2008) Serotonin receptors. Chem Rev 108:1614–1641PubMedCrossRefGoogle Scholar
  34. 34.
    Hannon J, Hoyer D (2008) Molecular biology of 5-HT receptors. Behav Brain Res 195:198–213PubMedCrossRefGoogle Scholar
  35. 35.
    McCorvy JD, Roth BL (2015) Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther 150:129–142PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Pazos A, Hoyer D, Palacios JM (1984) The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. Eur J Pharmacol 106:539–546PubMedCrossRefGoogle Scholar
  37. 37.
    Conn PJ, Sanders-Bush E (1985) Serotonin-stimulated phosphoinositide turnover: mediation by the S2 binding site in rat cerebral cortex but not in subcortical regions. J Pharmacol Exp Ther 234:195–203PubMedGoogle Scholar
  38. 38.
    Conn PJ, Sanders-Bush E, Hoffman BJ, Hartig PR (1986) A unique serotonin receptor in choroid plexus is linked to phosphatidylinositol turnover. Proc Natl Acad Sci U S A 83:4086–4088PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387:303–308PubMedCrossRefGoogle Scholar
  40. 40.
    Berg KA, Cropper JD, Niswender CM, Sanders-Bush E, Emeson RB, Clarke WP (2001) RNA-editing of the 5-HT(2C) receptor alters agonist-receptor-effector coupling specificity. Br J Pharmacol 134:386–392PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    McGrew L, Price RD, Hackler E, Chang MS, Sanders-Bush E (2004) RNA editing of the human serotonin 5-HT2C receptor disrupts transactivation of the small G-protein RhoA. Mol Pharmacol 65:252–256PubMedCrossRefGoogle Scholar
  42. 42.
    Price RD, Weiner DM, Chang MS, Sanders-Bush E (2001) RNA editing of the human serotonin 5-HT2C receptor alters receptor-mediated activation of G13 protein. J Biol Chem 276:44663–44668PubMedCrossRefGoogle Scholar
  43. 43.
    Nelson DL (2004) 5-HT5 receptors. Curr Drug Targets CNS Neurol Disord 3:53–58PubMedCrossRefGoogle Scholar
  44. 44.
    Rees S, den Daas I, Foord S, Goodson S, Bull D, Kilpatrick G, Lee M (1994) Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett 355:242–246PubMedCrossRefGoogle Scholar
  45. 45.
    Martin GR, Eglen RM, Hamblin MW, Hoyer D, Yocca F (1998) The structure and signalling properties of 5-HT receptors: an endless diversity? Trends Pharmacol Sci 19:2–4PubMedCrossRefGoogle Scholar
  46. 46.
    Cook EH Jr, Fletcher KE, Wainwright M, Marks N, Yan SY, Leventhal BL (1994) Primary structure of the human platelet serotonin 5-HT2A receptor: identify with frontal cortex serotonin 5-HT2A receptor. J Neurochem 63:465–469PubMedCrossRefGoogle Scholar
  47. 47.
    Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT (1997) Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907. Naunyn Schmiedebergs Arch Pharmacol 356:446–454PubMedCrossRefGoogle Scholar
  48. 48.
    Lopez-Gimenez JF, Vilaro MT, Palacios JM, Mengod G (2001) Mapping of 5-HT2A receptors and their mRNA in monkey brain: [3H]MDL100,907 autoradiography and in situ hybridization studies. J Comp Neurol 429:571–589PubMedCrossRefGoogle Scholar
  49. 49.
    Jakab RL, Goldman-Rakic PS (1998) 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci U S A 95:735–740PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Weber ET, Andrade R (2010) Htr2a Gene and 5-HT(2A) receptor expression in the cerebral cortex studied using genetically modified mice. Front Neurosci 4:36PubMedPubMedCentralGoogle Scholar
  51. 51.
    Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181PubMedCrossRefGoogle Scholar
  52. 52.
    Nichols DE (2016) Psychedelics. Pharmacol Rev 68:264–355PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C (2014) Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383:533–540PubMedCrossRefGoogle Scholar
  54. 54.
    Celada P, Puig M, Amargos-Bosch M, Adell A, Artigas F (2004) The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci 29:252–265PubMedPubMedCentralGoogle Scholar
  55. 55.
    Reddy DS (2013) The pathophysiological and pharmacological basis of current drug treatment of migraine headache. Expert Rev Clin Pharmacol 6:271–288PubMedCrossRefGoogle Scholar
  56. 56.
    Agundez JA, Garcia-Martin E, Alonso-Navarro H, Jimenez-Jimenez FJ (2013) Anti-Parkinson’s disease drugs and pharmacogenetic considerations. Expert Opin Drug Metab Toxicol 9:859–874PubMedCrossRefGoogle Scholar
  57. 57.
    Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, Gonzalez-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA (2013) The HIV antiretroviral drug Efavirenz has LSD-Like properties. Neuropsychopharmacology 38(12):2373–2384PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62:405–496PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Paoletti P (2011) Molecular basis of NMDA receptor functional diversity. Eur J Neurosci 33:1351–1365PubMedCrossRefGoogle Scholar
  60. 60.
    Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383–400PubMedCrossRefGoogle Scholar
  61. 61.
    Wang G, Gilbert J, Man HY (2012) AMPA receptor trafficking in homeostatic synaptic plasticity: functional molecules and signaling cascades. Neural Plast 2012:825364. PubMedPubMedCentralGoogle Scholar
  62. 62.
    Hunt DL, Castillo PE (2012) Synaptic plasticity of NMDA receptors: mechanisms and functional implications. Curr Opin Neurobiol 22:496–508PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Contractor A, Mulle C, Swanson GT (2011) Kainate receptors coming of age: milestones of two decades of research. Trends Neurosci 34:154–163PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Matute C (2011) Therapeutic potential of kainate receptors. CNS Neurosci Ther 17:661–669PubMedCrossRefGoogle Scholar
  65. 65.
    Sladeczek F, Pin JP, Recasens M, Bockaert J, Weiss S (1985) Glutamate stimulates inositol phosphate formation in striatal neurones. Nature 317:717–719PubMedCrossRefGoogle Scholar
  66. 66.
    Nicoletti F, Iadarola MJ, Wroblewski JT, Costa E (1986) Excitatory amino acid recognition sites coupled with inositol phospholipid metabolism: developmental changes and interaction with alpha 1-adrenoceptors. Proc Natl Acad Sci U S A 83:1931–1935PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Masu M, Tanabe Y, Tsuchida K, Shigemoto R, Nakanishi S (1991) Sequence and expression of a metabotropic glutamate receptor. Nature 349:760–765PubMedCrossRefGoogle Scholar
  68. 68.
    Houamed KM, Kuijper JL, Gilbert TL, Haldeman BA, O’Hara PJ, Mulvihill ER, Almers W, Hagen FS (1991) Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain. Science 252:1318–1321PubMedCrossRefGoogle Scholar
  69. 69.
    Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–1041PubMedCrossRefGoogle Scholar
  70. 70.
    Pin JP, Galvez T, Prezeau L (2003) Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther 98:325–354PubMedCrossRefGoogle Scholar
  71. 71.
    Pin JP, Kniazeff J, Goudet C, Bessis AS, Liu J, Galvez T, Acher F, Rondard P, Prezeau L (2004) The activation mechanism of class-C G-protein coupled receptors. Biol Cell 96:335–342PubMedCrossRefGoogle Scholar
  72. 72.
    Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237PubMedCrossRefGoogle Scholar
  73. 73.
    Aghajanian GK, Marek GJ (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36:589–599PubMedCrossRefGoogle Scholar
  74. 74.
    Aghajanian GK, Marek GJ (1999) Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825:161–171PubMedCrossRefGoogle Scholar
  75. 75.
    Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK (2000) Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 292:76–87PubMedGoogle Scholar
  76. 76.
    Fernando AB, Robbins TW (2011) Animal models of neuropsychiatric disorders. Annu Rev Clin Psychol 7:39–61PubMedCrossRefGoogle Scholar
  77. 77.
    Arguello PA, Gogos JA (2006) Modeling madness in mice: one piece at a time. Neuron 52:179–196PubMedCrossRefGoogle Scholar
  78. 78.
    Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Kellendonk C, Simpson EH, Kandel ER (2009) Modeling cognitive endophenotypes of schizophrenia in mice. Trends Neurosci 32:347–358PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Jones CA, Watson DJ, Fone KC (2011) Animal models of schizophrenia. Br J Pharmacol 164:1162–1194PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Young JW, Zhou X, Geyer MA (2010) Animal models of schizophrenia. Curr Top Behav Neurosci 4:391–433PubMedCrossRefGoogle Scholar
  82. 82.
    Canal CE, Morgan D (2012) Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Anal 4(7–8):556–576PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Hanks JB, Gonzalez-Maeso J (2013) Animal models of serotonergic psychedelics. ACS Chem Neurosci 4:33–42PubMedCrossRefGoogle Scholar
  84. 84.
    Moreno JL, Gonzalez-Maeso J (2013) Preclinical models of antipsychotic drug action. Int J Neuropsychopharmacol 16(10):2131–2144PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA (2007) Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53:439–452PubMedCrossRefGoogle Scholar
  86. 86.
    Gonzalez-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R, Gingrich JA, Sealfon SC (2003) Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci 23:8836–8843PubMedGoogle Scholar
  87. 87.
    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
  88. 88.
    Béïque J-C, Imad M, Mladenovic L, Gingrich JA, Andrade R (2007) Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci U S A 104:9870–9875PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    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
  90. 90.
    Celada P, Puig MV, Diaz-Mataix L, Artigas F (2008) The hallucinogen DOI reduces low-frequency oscillations in rat prefrontal cortex: reversal by antipsychotic drugs. Biol Psychiatry 64:392–400PubMedCrossRefGoogle Scholar
  91. 91.
    Marek GJ, Wright RA, Gewirtz JC, Schoepp DD (2001) A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience 105:379–392PubMedCrossRefGoogle Scholar
  92. 92.
    Scruggs JL, Patel S, Bubser M, Deutch AY (2000) DOI-induced activation of the cortex: dependence on 5-HT2A heteroceptors on thalamocortical glutamatergic neurons. J Neurosci 20:8846–8852PubMedGoogle Scholar
  93. 93.
    Barre A, Berthoux C, De Bundel D, Valjent E, Bockaert J, Marin P, Becamel C (2016) Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning. Proc Natl Acad Sci U S A 113(10):E1382–E1391PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Gewirtz JC, Marek GJ (2000) Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23:569–576PubMedCrossRefGoogle Scholar
  95. 95.
    Van der Kloot W (1991) The regulation of quantal size. Prog Neurobiol 36:93–130PubMedCrossRefGoogle Scholar
  96. 96.
    Lovinger DM, McCool BA (1995) Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3. J Neurophysiol 73:1076–1083PubMedCrossRefGoogle Scholar
  97. 97.
    Maggio R, Vogel Z, Wess J (1993) Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular “cross-talk” between G-protein-linked receptors. Proc Natl Acad Sci U S A 90:3103–3107PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W, Bettler B (1997) Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature 386:239–246PubMedCrossRefGoogle Scholar
  99. 99.
    Couve A, Filippov AK, Connolly CN, Bettler B, Brown DA, Moss SJ (1998) Intracellular retention of recombinant GABAB receptors. J Biol Chem 273:26361–26367PubMedCrossRefGoogle Scholar
  100. 100.
    Jones KA, Borowsky B, Tamm JA, Craig DA, Durkin MM, Dai M, Yao WJ, Johnson M, Gunwaldsen C, Huang LY, Tang C, Shen Q, Salon JA, Morse K, Laz T, Smith KE, Nagarathnam D, Noble SA, Branchek TA, Gerald C (1998) GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 396:674–679PubMedCrossRefGoogle Scholar
  101. 101.
    Kaupmann K, Malitschek B, Schuler V, Heid J, Froestl W, Beck P, Mosbacher J, Bischoff S, Kulik A, Shigemoto R, Karschin A, Bettler B (1998) GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature 396:683–687PubMedCrossRefGoogle Scholar
  102. 102.
    White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, Marshall FH (1998) Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature 396:679–682PubMedCrossRefGoogle Scholar
  103. 103.
    Kuner R, Kohr G, Grunewald S, Eisenhardt G, Bach A, Kornau HC (1999) Role of heteromer formation in GABAB receptor function. Science 283:74–77PubMedCrossRefGoogle Scholar
  104. 104.
    Margeta-Mitrovic M, Jan YN, Jan LY (2001) Function of GB1 and GB2 subunits in G protein coupling of GABA(B) receptors. Proc Natl Acad Sci U S A 98:14649–14654PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Margeta-Mitrovic M, Jan YN, Jan LY (2001) Ligand-induced signal transduction within heterodimeric GABA(B) receptor. Proc Natl Acad Sci U S A 98:14643–14648PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Margeta-Mitrovic M, Jan YN, Jan LY (2000) A trafficking checkpoint controls GABA(B) receptor heterodimerization. Neuron 27:97–106PubMedCrossRefGoogle Scholar
  107. 107.
    Milligan G (2013) The prevalence, maintenance and relevance of GPCR oligomerization. Mol Pharmacol 84(1):158–169PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Milligan G (2009) The role of dimerisation in the cellular trafficking of G-protein-coupled receptors. Curr Opin Pharmacol 10:23–29PubMedCrossRefGoogle Scholar
  109. 109.
    Milligan G (2009) G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol 158:5–14PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Gonzalez-Maeso J (2011) GPCR oligomers in pharmacology and signaling. Mol Brain 4:20PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Gonzalez-Maeso J (2014) Family a GPCR heteromers in animal models. Front Pharmacol 5:226PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Han Y, Moreira IS, Urizar E, Weinstein H, Javitch JA (2009) Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation. Nat Chem Biol 5:688–695PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Guo W, Urizar E, Kralikova M, Mobarec JC, Shi L, Filizola M, Javitch JA (2008) Dopamine D2 receptors form higher order oligomers at physiological expression levels. Embo J 27:2293–2304PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Guo W, Shi L, Javitch JA (2003) The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer. J Biol Chem 278:4385–4388PubMedCrossRefGoogle Scholar
  115. 115.
    Guo W, Shi L, Filizola M, Weinstein H, Javitch JA (2005) Crosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation. Proc Natl Acad Sci U S A 102:17495–17500PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    López-Giménez JF, Canals M, Pediani JD, Milligan G (2007) The alpha1b-adrenoceptor exists as a higher-order oligomer: effective oligomerization is required for receptor maturation, surface delivery, and function. Mol Pharmacol 71:1015–1029PubMedCrossRefGoogle Scholar
  117. 117.
    Carrillo JJ, Lopez-Gimenez JF, Milligan G (2004) Multiple interactions between transmembrane helices generate the oligomeric alpha1b-adrenoceptor. Mol Pharmacol 66:1123–1137PubMedCrossRefGoogle Scholar
  118. 118.
    Kniazeff J, Bessis A-S, Maurel D, Ansanay H, Prézeau L, Pin J-P (2004) Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat Struct Mol Biol 11:706–713PubMedCrossRefGoogle Scholar
  119. 119.
    El Moustaine D, Granier S, Doumazane E, Scholler P, Rahmeh R, Bron P, Mouillac B, Baneres JL, Rondard P, Pin JP (2012) Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling. Proc Natl Acad Sci U S A 109:16342–16347PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Xue L, Rovira X, Scholler P, Zhao H, Liu J, Pin JP, Rondard P (2015) Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer. Nat Chem Biol 11:134–140PubMedCrossRefGoogle Scholar
  121. 121.
    Whorton MR, Jastrzebska B, Park PS, Fotiadis D, Engel A, Palczewski K, Sunahara RK (2008) Efficient coupling of transducin to monomeric rhodopsin in a phospholipid bilayer. J Biol Chem 283:4387–4394PubMedCrossRefGoogle Scholar
  122. 122.
    Whorton MR, Bokoch MP, Rasmussen SG, Huang B, Zare RN, Kobilka B, Sunahara RK (2007) A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc Natl Acad Sci U S A 104:7682–7687PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Kuszak AJ, Pitchiaya S, Anand JP, Mosberg HI, Walter NG, Sunahara RK (2009) Purification and functional reconstitution of monomeric mu-opioid receptors: allosteric modulation of agonist binding by Gi2. J Biol Chem 284:26732–26741PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Rasmussen SGF, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah STA, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK (2011) Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477(7366):549–555PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Jordan BA, Devi LA (1999) G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399:697–700PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    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
  127. 127.
    Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, Lopez-Gimenez JF, Meana JJ, Benson DL, Gonzalez-Maeso J (2012) Identification of three residues essential for 5-HT2A-mGlu2 receptor heteromerization and its psychoactive behavioral function. J Biol Chem 287:44301–44319PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Rives ML, Vol C, Fukazawa Y, Tinel N, Trinquet E, Ayoub MA, Shigemoto R, Pin JP, Prezeau L (2009) Crosstalk between GABAB and mGlu1a receptors reveals new insight into GPCR signal integration. Embo J 28:2195–2208PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    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-HT(2A)-mGlu(2) and its relevance for cellular signaling cascades. Neuropharmacology 62(7):2184–2191PubMedCrossRefGoogle Scholar
  130. 130.
    Wright RA, Johnson BG, Zhang C, Salhoff C, Kingston AE, Calligaro DO, Monn JA, Schoepp DD, Marek GJ (2012) CNS distribution of metabotropic glutamate 2 and 3 receptors: transgenic mice and [(3)H]LY459477 autoradiography. Neuropharmacology 66:89–98PubMedCrossRefGoogle Scholar
  131. 131.
    Chan P, Gonzalez-Maeso J, Ruf F, Bishop DF, Hof PR, Sealfon SC (2005) Epsilon-Sarcoglycan immunoreactivity and mRNA expression in mouse brain. J Comp Neurol 482:50–73PubMedCrossRefGoogle Scholar
  132. 132.
    Chan P, Yuen T, Ruf F, Gonzalez-Maeso J, Sealfon SC (2005) Method for multiplex cellular detection of mRNAs using quantum dot fluorescent in situ hybridization. Nucleic Acids Res 33:e161PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, Mackerell AD Jr, Brezina V, Sealfon SC, Filizola M, Gonzalez-Maeso J, Logothetis DE (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147:1011–1023PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Moreno JL, Miranda-Azpiazu P, Garcia-Bea A, Younkin J, Cui M, Kozlenkov A, Ben-Ezra A, Voloudakis G, Fakira AK, Baki L, Ge Y, Georgakopoulos A, Moron JA, Milligan G, Lopez-Gimenez JF, Robakis NK, Logothetis DE, Meana JJ, Gonzalez-Maeso J (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Jastrzebska B, Fotiadis D, Jang GF, Stenkamp RE, Engel A, Palczewski K (2006) Functional and structural characterization of rhodopsin oligomers. J Biol Chem 281:11917–11922PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Lopez-Gimenez JF, Canals M, Pediani JD, Milligan G (2007) The alpha1b-adrenoceptor exists as a higher-order oligomer: effective oligomerization is required for receptor maturation, surface delivery, and function. Mol Pharmacol 71:1015–1029PubMedCrossRefGoogle Scholar
  137. 137.
    Bonaventura J, Navarro G, Casado-Anguera V, Azdad K, Rea W, Moreno E, Brugarolas M, Mallol J, Canela EI, Lluis C, Cortes A, Volkow ND, Schiffmann SN, Ferre S, Casado V (2015) Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer. Proc Natl Acad Sci U S A 112:E3609–E3618PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Wu B, Chien EYT, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC (2010) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330:1066–1071PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Huang J, Chen S, Zhang JJ, Huang XY (2013) Crystal structure of oligomeric beta1-adrenergic G protein-coupled receptors in ligand-free basal state. Nat Struct Mol Biol 20:419–425PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S (2012) Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature 485:321–326PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Gonzalez-Maeso J, Sealfon SC (2009) Psychedelics and schizophrenia. Trends Neurosci 32:225–232PubMedCrossRefGoogle Scholar
  142. 142.
    Oquendo MA, Russo SA, Underwood MD, Kassir SA, Ellis SP, Mann JJ, Arango V (2006) Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide. Biol Psychiatry 59:235–243PubMedCrossRefGoogle Scholar
  143. 143.
    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
  144. 144.
    Slipczuk L, Tomaiuolo M, Garagoli F, Weisstaub N, Katche C, Bekinschtein P, Medina JH (2013) Attenuating the persistence of fear memory storage using a single dose of antidepressant. Mol Psychiatry 18:7–8PubMedCrossRefGoogle Scholar
  145. 145.
    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
  146. 146.
    Morris BJ, Cochran SM, Pratt JA (2005) PCP: from pharmacology to modelling schizophrenia. Curr Opin Pharmacol 5:101–106PubMedCrossRefGoogle Scholar
  147. 147.
    Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH (2007) NMDA receptors and schizophrenia. Curr Opin Pharmacol 7:48–55PubMedCrossRefGoogle Scholar
  148. 148.
    Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC (2000) Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch. Gen. Psychiatry 57:1139–1147PubMedCrossRefGoogle Scholar
  149. 149.
    Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467PubMedCrossRefGoogle Scholar
  150. 150.
    Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ, Niciu MJ, Morgan PT, Surti TS, Bloch MH, Ramani R, Smith MA, Wang XJ, Krystal JH, Corlett PR (2012) NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci U S A 109:16720–16725PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C, Daumann J, Obradovic M, Kovar KA (2006) Inhibition of return in the human 5HT(2A) agonist and NMDA antagonist model of psychosis. Neuropsychopharmacology 31(2):431–441PubMedCrossRefGoogle Scholar
  152. 152.
    Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C, Obradovic M, Kovar KA (2006) Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry 38:301–311CrossRefGoogle Scholar
  153. 153.
    Reissig CJ, Carter LP, Johnson MW, Mintzer MZ, Klinedinst MA, Griffiths RR (2012) High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens. Psychopharmacology 223(1):1–15PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649PubMedCrossRefGoogle Scholar
  155. 155.
    Umbricht D, Koller R, Vollenweider FX, Schmid L (2002) Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers. Biol Psychiatry 51:400–406PubMedCrossRefGoogle Scholar
  156. 156.
    Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9:3897–3902PubMedCrossRefGoogle Scholar
  157. 157.
    Young BG (1974) A phenomenological comparison of LSD and schizophrenic states. Br J Psychiatry 124:64–74PubMedCrossRefGoogle Scholar
  158. 158.
    Hoch PH, Cattell JP, Pennes HH (1952) Effects of mescaline and lysergic acid (d-LSD-25). Am J Psychiatry 108:579–584PubMedCrossRefGoogle Scholar
  159. 159.
    Anastasopoulos G, Photiades H (1962) Effects of LSD-25 on relatives of schizophrenic patients. J Ment Sci 108:95–98PubMedGoogle Scholar
  160. 160.
    Hermle L, Funfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E, Fehrenbach RA, Spitzer M (1992) Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol Psychiatry 32:976–991PubMedCrossRefGoogle Scholar
  161. 161.
    Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, Tyacke RJ, Leech R, Malizia AL, Murphy K, Hobden P, Evans J, Feilding A, Wise RG, Nutt DJ (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 109:2138–2143PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH, Vollenweider FX, Brenneisen R, Muller F, Borgwardt S, Liechti ME (2015) Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry 78(8):544–553PubMedCrossRefGoogle Scholar
  163. 163.
    Quednow BB, Kometer M, Geyer MA, Vollenweider FX (2011) Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers. Neuropsychopharmacology 37(3):630–640PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Bradford AM, Savage KM, Jones DN, Kalinichev M (2010) Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics. Psychopharmacology (Berl) 212:155–170CrossRefGoogle Scholar
  165. 165.
    Yadav PN, Kroeze WK, Farrell MS, Roth BL (2011) Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo. J Pharmacol Exp Ther 339:99–105PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, Powell SB (2009) 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity in mice. Neuropsychopharmacology 34:1958–1967PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Halberstadt AL, Geyer MA (2010) LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT(2A) receptor. Psychopharmacology (Berl) 208:179–189CrossRefGoogle Scholar
  168. 168.
    Halberstadt AL, Geyer MA (2011) Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 61:364–381PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Halberstadt AL, Geyer MA (2013) Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement. Psychopharmacology (Berl) 227:727–739CrossRefGoogle Scholar
  170. 170.
    Halberstadt AL, Geyer MA (2014) Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response. Neuropharmacology 77:200–207PubMedCrossRefGoogle Scholar
  171. 171.
    Halberstadt AL, Koedood L, Powell SB, Geyer MA (2011) Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice. J Psychopharmacol 25:1548–1561PubMedCrossRefGoogle Scholar
  172. 172.
    Halberstadt AL, Powell SB, Geyer MA (2013) Role of the 5-HT(2)A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice. Neuropharmacology 70:218–227PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Halberstadt AL, Geyer MA (2010) LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT(2A) receptor. Psychopharmacology 208:179–189PubMedCrossRefGoogle Scholar
  174. 174.
    Halberstadt AL, Koedood L, Powell SB, Geyer MA (2011) Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice. J Psychopharmacol (Oxford) 25:1548–1561CrossRefGoogle Scholar
  175. 175.
    Marona-Lewicka D, Thisted RA, Nichols DE (2005) Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis. Psychopharmacology (Berl) 180:427–435CrossRefGoogle Scholar
  176. 176.
    Marona-Lewicka D, Nichols DE (2007) Further evidence that the delayed temporal dopaminergic effects of LSD are mediated by a mechanism different than the first temporal phase of action. Pharmacol Biochem Behav 87:453–461PubMedCrossRefGoogle Scholar
  177. 177.
    Nichols CD, Sanders-Bush E (2002) A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. Neuropsychopharmacology 26:634–642PubMedCrossRefGoogle Scholar
  178. 178.
    Nichols CD, Garcia EE, Sanders-Bush E (2003) Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration. Brain Res Mol Brain Res 111:182–188PubMedCrossRefGoogle Scholar
  179. 179.
    Abbas AI, Yadav PN, Yao W-D, Arbuckle MI, Grant SGN, Caron MG, Roth BL (2009) PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors. J Neurosci 29:7124–7136PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Canal CE, Olaghere da Silva UB, Gresch PJ, Watt EE, Sanders-Bush E, Airey DC (2010) The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen. Psychopharmacology (Berl) 209:163–174CrossRefGoogle Scholar
  181. 181.
    Wischhof L, Irrsack E, Dietz F, Koch M (2015) Maternal lipopolysaccharide treatment differentially affects 5-HT and mGlu2/3 receptor function in the adult male and female rat offspring. Neuropharmacology 97:275–288PubMedCrossRefGoogle Scholar
  182. 182.
    Malkova NV, Gallagher JJ, Yu CZ, Jacobs RE, Patterson PH (2014) Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia. Proc Natl Acad Sci U S A 111:E2492–E2500PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    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
  184. 184.
    Karaki S, Becamel C, Murat S, Mannoury la Cour C, Millan MJ, Prezeau L, Bockaert J, Marin P, Vandermoere F (2014) Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists. Mol Cell Proteomics 13:1273–1285PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Garcia EE, Smith RL, Sanders-Bush E (2007) Role of G(q) protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. Neuropharmacology 52:1671–1677PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    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
  187. 187.
    Zhai Y, George CA, Zhai J, Nisenbaum ES, Johnson MP, Nisenbaum LK (2003) Group II metabotropic glutamate receptor modulation of DOI-induced c-fos mRNA and excitatory responses in the cerebral cortex. Neuropsychopharmacology 28:45–52PubMedCrossRefGoogle Scholar
  188. 188.
    Benneyworth MA, Xiang Z, Smith RL, Garcia EE, Conn PJ, Sanders-Bush E (2007) A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol Pharmacol 72:477–484PubMedCrossRefGoogle Scholar
  189. 189.
    Delille HK, Mezler M, Marek GJ (2013) The two faces of the pharmacological interaction of mGlu2 and 5-HT(2)A—relevance of receptor heterocomplexes and interaction through functional brain pathways. Neuropharmacology 70:296–305PubMedCrossRefGoogle Scholar
  190. 190.
    Baki L, Fribourg M, Younkin J, Eltit JM, Moreno JL, Park G, Vysotskaya Z, Narahari A, Sealfon SC, Gonzalez-Maeso J, Logothetis DE (2016) Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells. Pflugers Arch 468(5):775–793PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Takahashi A, Camacho P, Lechleiter JD, Herman B (1999) Measurement of intracellular calcium. Physiol Rev 79:1089–1125PubMedCrossRefGoogle Scholar
  192. 192.
    Francesconi A, Duvoisin RM (1998) Role of the second and third intracellular loops of metabotropic glutamate receptors in mediating dual signal transduction activation. J Biol Chem 273:5615–5624PubMedCrossRefGoogle Scholar
  193. 193.
    Vidi P. A., Przybyla J. A., Hu C. D., Watts VJ (2010) Visualization of G protein-coupled receptor (GPCR) interactions in living cells using bimolecular fluorescence complementation (BiFC). Curr Protoc Neurosci Chapter 5:Unit 5.29Google Scholar
  194. 194.
    Medland SE, Jahanshad N, Neale BM, Thompson PM (2014) Whole-genome analyses of whole-brain data: working within an expanded search space. Nat Neurosci 17:791–800PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Liu W, Downing AC, Munsie LM, Chen P, Reed MR, Ruble CL, Landschulz KT, Kinon BJ, Nisenbaum LK (2010) Pharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia. Pharmacogenomics J 12(3):246–254PubMedCrossRefGoogle Scholar
  196. 196.
    Nisenbaum LK, Downing AM, Zhao F, Millen BA, Munsie L, Kinon BJ, Adams DH, Gomez JC, Penny MA (2016) Serotonin 2A receptor SNP rs7330461 association with treatment response to pomaglumetad methionil in patients with schizophrenia. J Pers Med 6(1).
  197. 197.
    Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 13:1102–1107PubMedCrossRefGoogle Scholar
  198. 198.
    Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, Jackson K, Kryzhanovskaya L, Jarkova N (2011) A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 31:349–355PubMedCrossRefGoogle Scholar
  199. 199.
    Adams DH, Zhang L, Millen BA, Kinon BJ, Gomez JC (2014) Pomaglumetad methionil (LY2140023 Monohydrate) and aripiprazole in patients with schizophrenia: a Phase 3, multicenter, double-blind comparison. Schizophr Res Treatment 2014:758212PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Adams DH, Kinon BJ, Baygani S, Millen BA, Velona I, Kollack-Walker S, Walling DP (2013) A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. BMC Psychiatry 13:143PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Kurita M, Holloway T, Garcia-Bea A, Kozlenkov A, Friedman AK, Moreno JL, Heshmati M, Golden SA, Kennedy PJ, Takahashi N, Dietz DM, Mocci G, Gabilondo AM, Hanks J, Umali A, Callado LF, Gallitano AL, Neve RL, Shen L, Buxbaum JD, Han MH, Nestler EJ, Meana JJ, Russo SJ, Gonzalez-Maeso J (2012) HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci 15:1245–1254PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Kinon BJ, Millen BA, Zhang L, McKinzie DL (2015) Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia. Biol Psychiatry 78(11):754–762PubMedCrossRefGoogle Scholar
  203. 203.
    Deep-Soboslay A, Akil M, Martin CE, Bigelow LB, Herman MM, Hyde TM, Kleinman JE (2005) Reliability of psychiatric diagnosis in postmortem research. Biol Psychiatry 57:96–101PubMedCrossRefGoogle Scholar
  204. 204.
    Deep-Soboslay A, Benes FM, Haroutunian V, Ellis JK, Kleinman JE, Hyde TM (2011) Psychiatric brain banking: three perspectives on current trends and future directions. Biol Psychiatry 69:104–112PubMedCrossRefGoogle Scholar
  205. 205.
    Reynolds GP, Rossor MN, Iversen LL (1983) Preliminary studies of human cortical 5-HT2 receptors and their involvement in schizophrenia and neuroleptic drug action. J Neural Transm Suppl 18:273–277PubMedGoogle Scholar
  206. 206.
    Mita T, Hanada S, Nishino N, Kuno T, Nakai H, Yamadori T, Mizoi Y, Tanaka C (1986) Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics. Biol Psychiatry 21:1407–1414PubMedCrossRefGoogle Scholar
  207. 207.
    Laruelle M, Abi-Dargham A, Casanova MF, Toti R, Weinberger DR, Kleinman JE (1993) Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. A postmortem study. Arch Gen Psychiatry 50:810–818PubMedCrossRefGoogle Scholar
  208. 208.
    Burnet PW, Eastwood SL, Harrison PJ (1996) 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 15:442–455PubMedCrossRefGoogle Scholar
  209. 209.
    Dean B, Hayes W (1996) Decreased frontal cortical serotonin2A receptors in schizophrenia. Schizophr Res 21:133–139PubMedCrossRefGoogle Scholar
  210. 210.
    Dean B, Hayes W, Hill C, Copolov D (1998) Decreased serotonin2A receptors in Brodmann’s area 9 from schizophrenic subjects. A pathological or pharmacological phenomenon? Mol Chem Neuropathol 34:133–145PubMedCrossRefGoogle Scholar
  211. 211.
    Dean B, Hussain T, Hayes W, Scarr E, Kitsoulis S, Hill C, Opeskin K, Copolov DL (1999) Changes in serotonin2A and GABA(A) receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. J Neurochem 72:1593–1599PubMedCrossRefGoogle Scholar
  212. 212.
    Matsumoto I, Inoue Y, Iwazaki T, Pavey G, Dean B (2005) 5-HT2A and muscarinic receptors in schizophrenia: a postmortem study. Neurosci Lett 379:164–168PubMedCrossRefGoogle Scholar
  213. 213.
    Dean B, Crossland N, Boer S, Scarr E (2008) Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia. Schizophr Res 104:185–197PubMedCrossRefGoogle Scholar
  214. 214.
    Kang K, Huang XF, Wang Q, Deng C (2009) Decreased density of serotonin 2A receptors in the superior temporal gyrus in schizophrenia—a postmortem study. Prog Neuropsychopharmacol Biol Psychiatry 33:867–871PubMedCrossRefGoogle Scholar
  215. 215.
    Dean B, Hayes W, Opeskin K, Naylor L, Pavey G, Hill C, Keks N, Copolov DL (1996) Serotonin2 receptors and the serotonin transporter in the schizophrenic brain. Behav Brain Res 73:169–175PubMedCrossRefGoogle Scholar
  216. 216.
    Marazziti D, Giannaccini G, Giromella A, Betti L, Pesce D, Nardi I, Rossi A, Lucacchini A, Cassano GB (2003) [3H]-ketanserin binding sites in different psychiatric disorders. Neurochem Int 42:511–516PubMedCrossRefGoogle Scholar
  217. 217.
    Muguruza C, Moreno JL, Umali A, Callado LF, Meana JJ, Gonzalez-Maeso J (2013) Dysregulated 5-HT(2A) receptor binding in postmortem frontal cortex of schizophrenic subjects. Eur Neuropsychopharmacol 23:852–864PubMedCrossRefGoogle Scholar
  218. 218.
    Bennett JP Jr, Enna SJ, Bylund DB, Gillin JC, Wyatt RJ, Snyder SH (1979) Neurotransmitter receptors in frontal cortex of schizophrenics. Arch Gen Psychiatry 36:927–934PubMedCrossRefGoogle Scholar
  219. 219.
    Whitaker PM, Crow TJ, Ferrier IN (1981) Tritiated LSD binding in frontal cortex in schizophrenia. Arch Gen Psychiatry 38:278–280PubMedCrossRefGoogle Scholar
  220. 220.
    Joyce JN, Shane A, Lexow N, Winokur A, Casanova MF, Kleinman JE (1993) Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 8:315–336PubMedCrossRefGoogle Scholar
  221. 221.
    Gurevich EV, Joyce JN (1997) Alterations in the cortical serotonergic system in schizophrenia: a postmortem study. Biol Psychiatry 42:529–545PubMedCrossRefGoogle Scholar
  222. 222.
    Erritzoe D, Rasmussen H, Kristiansen KT, Frokjaer VG, Haugbol S, Pinborg L, Baare W, Svarer C, Madsen J, Lublin H, Knudsen GM, Glenthoj BY (2008) Cortical and subcortical 5-HT(2A) receptor binding in neuroleptic-naive first-episode schizophrenic patients. Neuropsychopharmacology 33:2435–2441PubMedCrossRefGoogle Scholar
  223. 223.
    Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LH, Baare W, Svarer C, Lublin H, Knudsen GM, Glenthoj B (2010) Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia. Arch Gen Psychiatry 67:9–16PubMedCrossRefGoogle Scholar
  224. 224.
    Arora RC, Meltzer HY (1991) Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J Neural Transm Gen Sect 85:19–29PubMedCrossRefGoogle Scholar
  225. 225.
    Pralong D, Tomaskovic-Crook E, Opeskin K, Copolov D, Dean B (2000) Serotonin(2A) receptors are reduced in the planum temporale from subjects with schizophrenia. Schizophr Res 44:35–45PubMedCrossRefGoogle Scholar
  226. 226.
    Huot P, Johnston TH, Darr T, Hazrati LN, Visanji NP, Pires D, Brotchie JM, Fox SH (2010) Increased 5-HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Mov Disord 25:1399–1408PubMedCrossRefGoogle Scholar
  227. 227.
    Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, Jorgensen LM, Hansen M, Baandrup AO, Bache S, Svarer C, Kristensen JL, Gillings N, Madsen J, Knudsen GM (2014) Serotonin 2A receptor agonist binding in the human brain with [(1)(1)C]Cimbi-36. J Cereb Blood Flow Metab 34:1188–1196PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Ettrup A, Svarer C, McMahon B, da Cunha-Bang S, Lehel S, Moller K, Dyssegaard A, Ganz M, Beliveau V, Jorgensen LM, Gillings N, Knudsen GM (2016) Serotonin 2A receptor agonist binding in the human brain with [C]Cimbi-36: test-retest reproducibility and head-to-head comparison with the antagonist [F]altanserin. Neuroimage 130:167–174PubMedCrossRefGoogle Scholar
  229. 229.
    Joiner TE Jr, Brown JS, Wingate LR (2005) The psychology and neurobiology of suicidal behavior. Annu Rev Psychol 56:287–314PubMedCrossRefGoogle Scholar
  230. 230.
    Owen F, Cross AJ, Crow TJ, Deakin JF, Ferrier IN, Lofthouse R, Poulter M (1983) Brain 5-HT-2 receptors and suicide. Lancet 2:1256PubMedCrossRefGoogle Scholar
  231. 231.
    Crow TJ, Cross AJ, Cooper SJ, Deakin JF, Ferrier IN, Johnson JA, Joseph MH, Owen F, Poulter M, Lofthouse R et al (1984) Neurotransmitter receptors and monoamine metabolites in the brains of patients with Alzheimer-type dementia and depression, and suicides. Neuropharmacology 23:1561–1569PubMedCrossRefGoogle Scholar
  232. 232.
    Cheetham SC, Crompton MR, Katona CL, Horton RW (1988) Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res 443:272–280PubMedCrossRefGoogle Scholar
  233. 233.
    Arranz B, Eriksson A, Mellerup E, Plenge P, Marcusson J (1994) Brain 5-HT1A, 5-HT1D, and 5-HT2 receptors in suicide victims. Biol Psychiatry 35:457–463PubMedCrossRefGoogle Scholar
  234. 234.
    Lowther S, De Paermentier F, Crompton MR, Katona CL, Horton RW (1994) Brain 5-HT2 receptors in suicide victims: violence of death, depression and effects of antidepressant treatment. Brain Res 642:281–289PubMedCrossRefGoogle Scholar
  235. 235.
    Stockmeier CA, Dilley GE, Shapiro LA, Overholser JC, Thompson PA, Meltzer HY (1997) Serotonin receptors in suicide victims with major depression. Neuropsychopharmacology 16:162–173PubMedCrossRefGoogle Scholar
  236. 236.
    Rosel P, Arranz B, San L, Vallejo J, Crespo JM, Urretavizcaya M, Navarro MA (2000) Altered 5-HT(2A) binding sites and second messenger inositol trisphosphate (IP(3)) levels in hippocampus but not in frontal cortex from depressed suicide victims. Psychiatry Res 99:173–181PubMedCrossRefGoogle Scholar
  237. 237.
    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
  238. 238.
    Hrdina PD, Demeter E, Vu TB, Sotonyi P, Palkovits M (1993) 5-HT uptake sites and 5-HT2 receptors in brain of antidepressant-free suicide victims/depressives: increase in 5-HT2 sites in cortex and amygdala. Brain Res 614:37–44PubMedCrossRefGoogle Scholar
  239. 239.
    Gross-Isseroff R, Salama D, Israeli M, Biegon A (1990) Autoradiographic analysis of [3H]ketanserin binding in the human brain postmortem: effect of suicide. Brain Res 507:208–215PubMedCrossRefGoogle Scholar
  240. 240.
    Turecki G, Briere R, Dewar K, Antonetti T, Lesage AD, Seguin M, Chawky N, Vanier C, Alda M, Joober R, Benkelfat C, Rouleau GA (1999) Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry 156:1456–1458PubMedGoogle Scholar
  241. 241.
    Moreno JL, Seto J, Hanks JB, Gonzalez-Maeso J (2015) Techniques for the study of GPCR heteromerization in living cells and animal models. Neuromethods 95:21–36CrossRefGoogle Scholar
  242. 242.
    Strange PG (1998) Three-state and two-state models. Trends Pharmacol Sci 19:85–86PubMedCrossRefGoogle Scholar
  243. 243.
    Strange PG (2008) Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors. Br J Pharmacol 153:1353–1363PubMedPubMedCentralCrossRefGoogle Scholar
  244. 244.
    Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Moller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Muhleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nothen MM, Peltonen L, Collier DA, St Clair D, Stefansson K, Kahn RS, Linszen DH, van Os J, Wiersma D, Bruggeman R, Cahn W, de Haan L, Krabbendam L, Myin-Germeys I (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455:232–236PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, Werge T, Pietilainen OP, Mors O, Mortensen PB, Sigurdsson E, Gustafsson O, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Suvisaari J, Lonnqvist J, Paunio T, Borglum AD, Hartmann A, Fink-Jensen A, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Bottcher Y, Olesen J, Breuer R, Moller HJ, Giegling I, Rasmussen HB, Timm S, Mattheisen M, Bitter I, Rethelyi JM, Magnusdottir BB, Sigmundsson T, Olason P, Masson G, Gulcher JR, Haraldsson M, Fossdal R, Thorgeirsson TE, Thorsteinsdottir U, Ruggeri M, Tosato S, Franke B, Strengman E, Kiemeney LA, Melle I, Djurovic S, Abramova L, Kaleda V, Sanjuan J, de Frutos R, Bramon E, Vassos E, Fraser G, Ettinger U, Picchioni M, Walker N, Toulopoulou T, Need AC, Ge D, Yoon JL, Shianna KV, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Carracedo A, Arango C, Costas J, Jonsson EG, Terenius L, Agartz I, Petursson H, Nothen MM, Rietschel M, Matthews PM, Muglia P, Peltonen L, St Clair D, Goldstein DB, Stefansson K, Collier DA (2009) Common variants conferring risk of schizophrenia. Nature 460:744–747PubMedPubMedCentralGoogle Scholar
  246. 246.
    Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–752PubMedGoogle Scholar
  247. 247.
    Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320:539–543PubMedCrossRefGoogle Scholar
  248. 248.
    Consortium TIS (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241CrossRefGoogle Scholar
  249. 249.
    Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427PubMedCentralCrossRefGoogle Scholar
  250. 250.
    Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, O'Dushlaine C, Chambert K, Bergen SE, Kahler A, Duncan L, Stahl E, Genovese G, Fernandez E, Collins MO, Komiyama NH, Choudhary JS, Magnusson PK, Banks E, Shakir K, Garimella K, Fennell T, DePristo M, Grant SG, Haggarty SJ, Gabriel S, Scolnick EM, Lander ES, Hultman CM, Sullivan PF, McCarroll SA, Sklar P (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506:185–190PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B, McCarroll SA (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530:177–183PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Lewis DA, Levitt P (2002) Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 25:409–432PubMedCrossRefGoogle Scholar
  253. 253.
    Cardno AG, Gottesman II (2000) Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 97:12–17PubMedCrossRefGoogle Scholar
  254. 254.
    Gottesman II, Erlenmeyer-Kimling L (2001) Family and twin strategies as a head start in defining prodromes and endophenotypes for hypothetical early-interventions in schizophrenia. Schizophr Res 51:93–102PubMedCrossRefGoogle Scholar
  255. 255.
    Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, Babulas VP, Susser ES (2004) Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 61:774–780PubMedCrossRefGoogle Scholar
  256. 256.
    Menninger KA (1919) Psychoses associated with influenza. J. Am. Med. Assoc. 72:235–241CrossRefGoogle Scholar
  257. 257.
    Yudofsky SC (2009) Contracting schizophrenia: lessons from the influenza epidemic of 1918-1919. JAMA 301:324–326PubMedCrossRefGoogle Scholar
  258. 258.
    Brown AS, Cohen P, Harkavy-Friedman J, Babulas V, Malaspina D, Gorman JM, Susser ESAE (2001) Bennett research award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biol Psychiatry 49:473–486PubMedCrossRefGoogle Scholar
  259. 259.
    Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA (2009) Association between prenatal exposure to bacterial infection and risk of schizophrenia. Schizophr Bull 35:631–637PubMedCrossRefGoogle Scholar
  260. 260.
    Brown AS, Schaefer CA, Quesenberry CP Jr, Liu L, Babulas VP, Susser ES (2005) Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am J Psychiatry 162:767–773PubMedCrossRefGoogle Scholar
  261. 261.
    van Os J, Selten JP (1998) Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. Br J Psychiatry 172:324–326PubMedCrossRefGoogle Scholar
  262. 262.
    Malaspina D, Corcoran C, Kleinhaus KR, Perrin MC, Fennig S, Nahon D, Friedlander Y, Harlap S (2008) Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. BMC Psychiatry 8:71PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Susser E, St Clair D, He L (2008) Latent effects of prenatal malnutrition on adult health: the example of schizophrenia. Ann N Y Acad Sci 1136:185–192PubMedCrossRefGoogle Scholar
  264. 264.
    Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN, Kenny LC, Mortensen PB (2008) Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry 65:146–152PubMedCrossRefGoogle Scholar
  265. 265.
    Moreno JL, Kurita M, Holloway T, Lopez J, Cadagan R, Martinez-Sobrido L, Garcia-Sastre A, Gonzalez-Maeso J (2011) Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT2A and mGlu2 receptors in the adult offspring. J Neurosci 31:1863–1872PubMedPubMedCentralCrossRefGoogle Scholar
  266. 266.
    Akatsu S, Ishikawa C, Takemura K, Ohtani A, Shiga T (2015) Effects of prenatal stress and neonatal handling on anxiety, spatial learning and serotonergic system of male offspring mice. Neurosci Res 101:15–23PubMedCrossRefGoogle Scholar
  267. 267.
    Wang Y, Ma Y, Hu J, Cheng W, Jiang H, Zhang X, Li M, Ren J, Li X (2015) Prenatal chronic mild stress induces depression-like behavior and sex-specific changes in regional glutamate receptor expression patterns in adult rats. Neuroscience 301:363–374PubMedCrossRefGoogle Scholar
  268. 268.
    Holloway T, Moreno JL, Umali A, Rayannavar V, Hodes GE, Russo SJ, Gonzalez-Maeso J (2013) Prenatal stress induces schizophrenia-like alterations of serotonin 2A and metabotropic glutamate 2 receptors in the adult offspring: role of maternal immune system. J Neurosci 33:1088–1098PubMedPubMedCentralCrossRefGoogle Scholar
  269. 269.
    Pershing ML, Bortz DM, Pocivavsek A, Fredericks PJ, Jorgensen CV, Vunck SA, Leuner B, Schwarcz R, Bruno JP (2015) Elevated levels of kynurenic acid during gestation produce neurochemical, morphological, and cognitive deficits in adulthood: implications for schizophrenia. Neuropharmacology 90:33–41PubMedCrossRefGoogle Scholar
  270. 270.
    Nasca C, Zelli D, Bigio B, Piccinin S, Scaccianoce S, Nistico R, McEwen BS (2015) Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity. Proc Natl Acad Sci U S A 112:14960–14965PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Maple AM, Zhao X, Elizalde DI, McBride AK, Gallitano AL (2015) Htr2a expression responds rapidly to environmental stimuli in an Egr3-Dependent manner. ACS Chem Neurosci 6(7):1137–1142PubMedPubMedCentralCrossRefGoogle Scholar
  272. 272.
    Klein AB, Ultved L, Adamsen D, Santini MA, Tobena A, Fernandez-Teruel A, Flores P, Moreno M, Cardona D, Knudsen GM, Aznar S, Mikkelsen JD (2014) 5-HT(2A) and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains. Neuroscience 263:36–45PubMedCrossRefGoogle Scholar
  273. 273.
    Jorgensen CV, Jacobsen JP, Caron MG, Klein AB, Knudsen GM, Mikkelsen JD (2013) Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice. Neurosci Lett 555:118–122PubMedPubMedCentralCrossRefGoogle Scholar
  274. 274.
    Chiu HY, Chan MH, Lee MY, Chen ST, Zhan ZY, Chen HH (2014) Long-lasting alterations in 5-HT2A receptor after a binge regimen of methamphetamine in mice. Int J Neuropsychopharmacol 17(10):1647–1658PubMedCrossRefGoogle Scholar
  275. 275.
    Chen YW, Lin HC, Ng MC, Hsiao YH, Wang CC, Gean PW, Chen PS (2014) Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism. Front Behav Neurosci 8:219PubMedPubMedCentralGoogle Scholar
  276. 276.
    Zhou R, Chen F, Feng X, Zhou L, Li Y, Chen L (2015) Perinatal exposure to low-dose of bisphenol a causes anxiety-like alteration in adrenal axis regulation and behaviors of rat offspring: a potential role for metabotropic glutamate 2/3 receptors. J Psychiatr Res 64:121–129PubMedCrossRefGoogle Scholar
  277. 277.
    Holloway T, Gonzalez-Maeso J (2015) Epigenetic mechanisms of serotonin signaling. ACS Chem Neurosci 6:1099–1109PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Physiology and BiophysicsVirginia Commonwealth University School of MedicineRichmondUSA

Personalised recommendations