Advertisement

Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways

  • Juan F. López-Giménez
  • Javier González-Maeso
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 36)

Abstract

The neuropsychological effects of naturally occurring psychoactive chemicals have been recognized for millennia. Hallucinogens, which include naturally occurring chemicals such as mescaline and psilocybin, as well as synthetic compounds, such as lysergic acid diethylamide (LSD), induce profound alterations of human consciousness, emotion, and cognition. The discovery of the hallucinogenic effects of LSD and the observations that LSD and the endogenous ligand serotonin share chemical and pharmacological profiles led to the suggestion that biogenic amines like serotonin were involved in the psychosis of mental disorders such as schizophrenia. Although they bind other G protein-coupled receptor (GPCR) subtypes, studies indicate that several effects of hallucinogens involve agonist activity at the serotonin 5-HT2A receptor. In this chapter, we review recent advances in understanding hallucinogen drug action through characterization of structure, neuroanatomical location, and function of the 5-HT2A receptor.

Keywords

Serotonin 5-HT2A receptor G protein-coupled receptor (GPCR) Lysergic acid diethylamide (LSD) Psilocin Psilocybin Mescaline Schizophrenia Psychosis Hallucinogen Psychedelics Antipsychotics 

Notes

Acknowledgements

The preparation of this review article has been supported at least in part by the National Institutes of Health R01MH084894 and R01MH111940 (J.G.M.) and the Spanish Government SAF2010-15663 (J.F.L.G.).

References

  1. 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 29:7124–7136PubMedPubMedCentralGoogle Scholar
  2. Adams LM, Geyer MA (1985) Patterns of exploration in rats distinguish lisuride from lysergic acid diethylamide. Pharmacol Biochem Behav 23:461–468PubMedGoogle Scholar
  3. Aghajanian GK (2009) Modeling, “psychosis” in vitro by inducing disordered neuronal network activity in cortical brain slices. Psychopharmacology 206:575–585PubMedPubMedCentralGoogle Scholar
  4. Aghajanian GK, Marek GJ (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21:16S–23SPubMedGoogle Scholar
  5. Aghajanian GK, Marek GJ (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Brain Res Rev 31:302–312Google Scholar
  6. Aghajanian GK, Foote WE, Sheard MH (1968) Lysergic acid diethylamide: sensitive neuronal units in the midbrain raphe. Science 161:706–708PubMedGoogle Scholar
  7. Appel NM, Mitchell WM, Garlick RK, Glennon RA, Teitler M, De Souza EB (1990) Autoradiographic characterization of (+-)-1-(2,5-dimethoxy-4-[125I] iodophenyl)-2-aminopropane ([125I]DOI) binding to 5-HT2 and 5-HT1c receptors in rat brain. J Pharmacol Exp Ther 255:843–857PubMedGoogle Scholar
  8. Audet M, Bouvier M (2012) Restructuring G-protein-coupled receptor activation. Cell 151:14–23PubMedGoogle Scholar
  9. 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 468:775–793PubMedPubMedCentralGoogle Scholar
  10. Barclay Z, Dickson L, Robertson DN, Johnson MS, Holland PJ, Rosie R, Sun L, Fleetwood-Walker S, Lutz EM, Mitchell R (2011) 5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail. Biochem J 436:651–660Google Scholar
  11. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedGoogle Scholar
  12. Becamel C, Figge A, Poliak S, Dumuis A, Peles E, Bockaert J, Lubbert H, Ullmer C (2001) Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1. J Biol Chem 276:12974–12982PubMedGoogle Scholar
  13. Becamel C, Alonso G, Galeotti N, Demey E, Jouin P, Ullmer C, Dumuis A, Bockaert J, Marin P (2002a) Synaptic multiprotein complexes associated with 5-HT(2C) receptors: a proteomic approach. EMBO J 21:2332–2342PubMedPubMedCentralGoogle Scholar
  14. Becamel C, Galeotti N, Poncet J, Jouin P, Dumuis A, Bockaert J, Marin P (2002b) A proteomic approach based on peptide affinity chromatography, 2-dimensional electrophoresis and mass spectrometry to identify multiprotein complexes interacting with membrane-bound receptors. Biol Proced Online 4:94–104PubMedPubMedCentralGoogle Scholar
  15. Becamel C, Gavarini S, Chanrion B, Alonso G, Galeotti N, Dumuis A, Bockaert J, Marin P (2004) The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. J Biol Chem 279:20257–20266PubMedGoogle Scholar
  16. Beique JC, 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 104:9870–9875PubMedPubMedCentralGoogle Scholar
  17. Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP (1998) Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol 54:94–104Google Scholar
  18. Berger M, Gray JA, Roth BL (2009) The expanded biology of serotonin. Annu Rev Med 60:355–366PubMedPubMedCentralGoogle Scholar
  19. Bhattacharya A, Sankar S, Panicker MM (2010) Differences in the C-terminus contribute to variations in trafficking between rat and human 5-HT(2A) receptor isoforms: identification of a primate-specific tripeptide ASK motif that confers GRK-2 and beta arrestin-2 interactions. J Neurochem 112:723–732PubMedGoogle Scholar
  20. Bhattacharyya S, Puri S, Miledi R, Panicker MM (2002) Internalization and recycling of 5-HT2A receptors activated by serotonin and protein kinase C-mediated mechanisms. Proc Natl Acad Sci U S A 99:14470–14475PubMedPubMedCentralGoogle Scholar
  21. Bouvier M, Hebert TE (2014) CrossTalk proposal: weighing the evidence for Class A GPCR dimers, the evidence favours dimers. J Physiol 592:2439–2441PubMedPubMedCentralGoogle Scholar
  22. Canal CE (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 …. Drug Testing and AnalysisGoogle Scholar
  23. 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 209:163–174PubMedPubMedCentralGoogle Scholar
  24. 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 64:392–400PubMedPubMedCentralGoogle Scholar
  25. 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 1–12Google Scholar
  26. Clark AJ (1933) The mode of action of drugs on cellsGoogle Scholar
  27. Dahlström A, Fuxe K (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand Suppl SUPPL 232:231–255Google Scholar
  28. De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem 255:7108–7117PubMedGoogle Scholar
  29. 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 1–8Google Scholar
  30. Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M (1998) Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors. Psychopharmacology 136:409–414PubMedGoogle Scholar
  31. Erhlich P (1913) Chemotherapeutics: scientific principles, methods and results. Lancet 2:445–451Google Scholar
  32. Fantegrossi WE, Murnane KS, Reissig CJ (2008) The behavioral pharmacology of hallucinogens. Biochem Pharmacol 75:17–33Google Scholar
  33. Ferguson SS (2001) Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 53:1–24PubMedGoogle Scholar
  34. Ferre S, Casado V, Devi LA, Filizola M, Jockers R, Lohse MJ, Milligan G, Pin JP, Guitart X (2014) G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev 66:413–434PubMedPubMedCentralGoogle Scholar
  35. Florian JA, Watts SW (1998) Integration of mitogen-activated protein kinase kinase activation in vascular 5-hydroxytryptamine2A receptor signal transduction. J Pharmacol Exp Ther 284:346–355PubMedGoogle Scholar
  36. Frederick A. L., Yano H., Trifilieff P, Vishwasrao HD, Biezonski D, Meszaros J, Urizar E, Sibley DR, Kellendonk C, Sonntag KC, Graham DL, Colbran RJ, Stanwood GD, Javitch JA (2015) Evidence against dopamine D1/D2 receptor heteromers. Mol PsychiatryPubMedPubMedCentralGoogle Scholar
  37. 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 147:1011–1023PubMedPubMedCentralGoogle Scholar
  38. Gaddum JH, Picarelli ZP (1957) Two kinds of tryptamine receptor. Br J Pharmacol Chemother 12:323–328PubMedPubMedCentralGoogle Scholar
  39. 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 52:1671–1677PubMedPubMedCentralGoogle Scholar
  40. Gerfen CR (1992) The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci 15:133–139PubMedGoogle Scholar
  41. Gewirtz JC, Marek GJ (2000) Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23:569–576Google Scholar
  42. Gewirtz JC, Chen AC, Terwilliger R, Duman RC, Marek GJ (2002) Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. Pharmacol Biochem Behav 73:317–326PubMedPubMedCentralGoogle Scholar
  43. Glennon RA, Titeler M, McKenney JD (1984) Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 35:2505–2511Google Scholar
  44. Glennon RA, Titeler M, Young R (1986) Structure-activity relationships and mechanism of action of hallucinogenic agents based on drug discrimination and radioligand binding studies. Psychopharmacol Bull 22:953–958PubMedGoogle Scholar
  45. Gonzalez-Maeso J (2011) GPCR oligomers in pharmacology and signaling. Mol Brain 4:20PubMedPubMedCentralGoogle Scholar
  46. 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 23:8836–8843PubMedPubMedCentralGoogle Scholar
  47. 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 53:439–452Google Scholar
  48. 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 452:93–97PubMedPubMedCentralGoogle Scholar
  49. Graybiel AM (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci 13:244–254PubMedGoogle Scholar
  50. Green AR (2008) Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK. Br J Pharmacol 154:1583–1599PubMedPubMedCentralGoogle Scholar
  51. Griebel G, Holsboer F (2012) Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning? Nat Rev Drug Discov 11:462–478PubMedGoogle Scholar
  52. Halberstadt AL (2015) Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res 277C:99–120Google Scholar
  53. Hanks JB, Gonzalez-Maeso J (2013) Animal models of serotonergic psychedelics. ACS Chem Neurosci 4:33–42Google Scholar
  54. Hannon J, Hoyer D (2008) Molecular biology of 5-HT receptors. Behav Brain Res 195:198–213PubMedGoogle Scholar
  55. Hanyaloglu AC, von Zastrow M (2008) Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu Rev Pharmacol Toxicol 48:537–568PubMedGoogle Scholar
  56. Hill SJ, Baker JG, Rees S (2001) Reporter-gene systems for the study of G-protein-coupled receptors. Curr Opin Pharmacol 1:526–532PubMedGoogle Scholar
  57. Hofmann A (1979) How LSD originated. J Psychedelic Drugs 11:53–60PubMedPubMedCentralGoogle Scholar
  58. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46:157–203PubMedGoogle Scholar
  59. Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554PubMedGoogle Scholar
  60. 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 20:419–425PubMedPubMedCentralGoogle Scholar
  61. Irannejad R, Tomshine JC, Tomshine JR, Chevalier M, Mahoney JP, Steyaert J, Rasmussen SG, Sunahara RK, El-Samad H, Huang B, von Zastrow M (2013) Conformational biosensors reveal GPCR signalling from endosomes. Nature 495:534–538PubMedGoogle Scholar
  62. Johnson MP, Siegel BW, Carr AA (1996) [3H]MDL 100,907: a novel selective 5-HT2A receptor ligand. Naunyn Schmiedebergs Arch Pharmacol 354:205–209PubMedGoogle Scholar
  63. 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 13:1273–1285PubMedPubMedCentralGoogle Scholar
  64. Katritch V, Cherezov V, Stevens RC (2013) Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol 53:531–556PubMedGoogle Scholar
  65. Kenakin T (1995) Agonist-receptor efficacy. II. Agonist trafficking of receptor signals. Trends Pharmacol Sci 16:232–238PubMedGoogle Scholar
  66. Kenakin T (1997) Agonist-specific receptor conformations. Trends Pharmacol Sci 18:416–417PubMedGoogle Scholar
  67. Kenakin T (2002) Drug efficacy at G protein-coupled receptors. Annu Rev Pharmacol Toxicol 42:349–379PubMedGoogle Scholar
  68. Kiu H, Nicholson SE (2012) Biology and significance of the JAK/STAT signalling pathways. Growth Factors 30:88–106PubMedPubMedCentralGoogle Scholar
  69. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH (1995) Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269:1737–1740PubMedGoogle Scholar
  70. Krebs TS, Johansen PO (2012) Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol 26:994–1002PubMedPubMedCentralGoogle Scholar
  71. Kurrasch-Orbaugh DM, Watts VJ, Barker EL, Nichols DE (2003a) Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves. J Pharmacol Exp Ther 304:229–237PubMedPubMedCentralGoogle Scholar
  72. Kurrasch-Orbaugh DM, Parrish JC, Watts VJ, Nichols DE (2003b) A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases. J Neurochem 86:980–991PubMedPubMedCentralGoogle Scholar
  73. 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 284:26732–26741PubMedPubMedCentralGoogle Scholar
  74. Lambert NA, Javitch JA (2014) CrossTalk opposing view: weighing the evidence for class A GPCR dimers, the jury is still out. J Physiol 592:2443–2445PubMedPubMedCentralGoogle Scholar
  75. Langley JN (1909) On the contraction of muscle, chiefly in relation to the presence of ‘receptive’ substances. J Physiol 39:235–295PubMedPubMedCentralGoogle Scholar
  76. Lee Y, Duman RS, Marek GJ (2006) The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression. Neurosci Lett 398:328–332PubMedGoogle Scholar
  77. Lee MY, Chiang CC, Chiu HY, Chan MH, Chen HH (2014) N-acetylcysteine modulates hallucinogenic 5-HT receptor agonist-mediated responses: behavioral, molecular, and electrophysiological studies. NeuropharmacologyGoogle Scholar
  78. Lefkowitz RJ, Cotecchia S, Samama P, Costa T (1993) Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol Sci 14:303–307PubMedGoogle Scholar
  79. 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 356:446–454PubMedGoogle Scholar
  80. Lopez-Gimenez JF, Vilaro MT, Palacios JM, Mengod G (1998) [3H]MDL 100,907 labels 5-HT2A serotonin receptors selectively in primate brain. Neuropharmacology 37:1147–1158PubMedGoogle Scholar
  81. Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT (1999) Human striosomes are enriched in 5-HT2A receptors: autoradiographical visualization with [3H]MDL100,907,[125I](±)DOI and [3H]ketanserin. Eur J Neurosci 11:3761–3765PubMedGoogle Scholar
  82. 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 429:571–589PubMedPubMedCentralGoogle Scholar
  83. Luttrell LM (2008) Reviews in molecular biology and biotechnology: transmembrane signaling by G protein-coupled receptors. Mol Biotechnol 39:239–264PubMedGoogle Scholar
  84. Luttrell LM, Lefkowitz RJ (2002) The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 115:455–465PubMedGoogle Scholar
  85. 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:E2492–2500PubMedPubMedCentralGoogle Scholar
  86. 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 485:321–326PubMedPubMedCentralGoogle Scholar
  87. 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 292:76–87Google Scholar
  88. 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 105:379–392PubMedPubMedCentralGoogle Scholar
  89. Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE (2002) Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats. Psychopharmacology 164:93–107PubMedGoogle Scholar
  90. 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 21:9856–9866PubMedPubMedCentralGoogle Scholar
  91. Mengod G, Vilaro MT, Cortes R, Lopez-Gimenez JF, Raurich A, Palacios JM (2006) Chemical neuroanatomy of 5-HT receptor subtypes in the mammalian brain. In Roth BL (ed) serotonin T, and therapeutics rFmpth. Humana Press, pp 319–364Google Scholar
  92. Millan MJ, Marin P, Bockaert J, la Cour CM (2008) Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci 29:454–464PubMedGoogle Scholar
  93. Milligan G (2013) The prevalence, maintenance and relevance of GPCR oligomerization. Mol Pharmacol 158–169 (Epub ahead of print)Google Scholar
  94. Mitchell R, McCulloch D, Lutz E, Johnson M, MacKenzie C, Fennell M, Fink G, Zhou W, Sealfon SC (1998) Rhodopsin-family receptors associate with small G proteins to activate phospholipase D. Nature 392:411–414PubMedGoogle Scholar
  95. Mohammad-Zadeh LF, Moses L, Gwaltney-Brant SM (2008) Serotonin: a review. J Vet Pharmacol Ther 31:187–199PubMedGoogle Scholar
  96. Mokler DJ, Commissaris RL, Warner MR, Rech RH (1983) Blockade of the behavioral effects of lysergic acid diethylamide, 2,5-dimethoxy-4-methylamphetamine, quipazine and lisuride by 5-hydroxytryptamine antagonists. J Pharmacol Exp Ther 227:557–562PubMedGoogle Scholar
  97. Moreno FA, Wiegand CB, Taitano EK, Delgado PL (2006) Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry 67:1735–1740PubMedPubMedCentralGoogle Scholar
  98. 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 493:76–79PubMedPubMedCentralGoogle Scholar
  99. 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-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A.mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem 287:44301–44319PubMedPubMedCentralGoogle Scholar
  100. 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:ra5PubMedPubMedCentralGoogle Scholar
  101. 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 23:852–864PubMedGoogle Scholar
  102. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181Google Scholar
  103. Nichols DE, Nichols CD (2008) Serotonin receptors. Chem Rev 108:1614–1641PubMedGoogle Scholar
  104. Nutt DJ, King LA, Nichols DE (2013) Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nat Rev Neurosci 14:577–585PubMedGoogle Scholar
  105. Oldham WM, Hamm HE (2008) Heterotrimeric G protein activation by G-protein-coupled receptors. Nat Rev Mol Cell Biol 9:60–71PubMedGoogle Scholar
  106. Oufkir T, Arseneault M, Sanderson JT, Vaillancourt C (2010) The 5-HT 2A serotonin receptor enhances cell viability, affects cell cycle progression and activates MEK-ERK1/2 and JAK2-STAT3 signalling pathways in human choriocarcinoma cell lines. Placenta 31:439–447PubMedGoogle Scholar
  107. Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5:993–996PubMedGoogle Scholar
  108. Pazos A, Cortes R, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346:231–249Google Scholar
  109. Pazos A, Probst A, Palacios JM (1987) Serotonin receptors in the human brain–IV. Autoradiographic mapping of serotonin-2 receptors. Neuroscience 21:123–139Google Scholar
  110. 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
  111. Pierce KL, Premont RT, Lefkowitz RJ (2002) Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3:639–650PubMedGoogle Scholar
  112. Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ (1999) Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol 128:13–20PubMedPubMedCentralGoogle Scholar
  113. Preller KH, Pokorny T, Hock A, Kraehenmann R, Stampfli P, Seifritz E, Scheidegger M, Vollenweider FX (2016) Effects of serotonin 2A/1A receptor stimulation on social exclusion processing. Proc Natl Acad Sci U S A 113:5119–5124PubMedPubMedCentralGoogle Scholar
  114. Preller KH, Herdener M, Pokorny T, Planzer A, Kraehenmann R, Stampfli P, Liechti ME, Seifritz E, Vollenweider FX (2017) The fabric of meaning and subjective effects in lsd-induced states depend on serotonin 2a receptor activation. Curr Biol 27:451–457PubMedGoogle Scholar
  115. 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 13:870–882PubMedPubMedCentralGoogle Scholar
  116. Rapport MM, Green AA, Page IH (1948) Serum vasoconstrictor, serotonin; isolation and characterization. J Biol Chem 176:1243–1251PubMedGoogle Scholar
  117. Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN (2001) Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 92:179–212PubMedGoogle Scholar
  118. Reid G, Rand M (1952) Pharmacological actions of synthetic 5-hydroxytryptamine (serotonin, thrombocytin). Nature 169:801–802PubMedGoogle Scholar
  119. 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 28:2195–2208PubMedPubMedCentralGoogle Scholar
  120. Robertson DN, Johnson MS, Moggach LO, Holland PJ, Lutz EM, Mitchell R (2003) Selective interaction of ARF1 with the carboxy-terminal tail domain of the 5-HT2A receptor. Mol Pharmacol 64:1239–1250PubMedGoogle Scholar
  121. Rosenbaum DM, Rasmussen SG, Kobilka BK (2009) The structure and function of G-protein-coupled receptors. Nature 459:356–363PubMedPubMedCentralGoogle Scholar
  122. Santini MA, Ratner C, Aznar S, Klein AB, Knudsen GM, Mikkelsen JD (2013) Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia. J Neurosci Res 91:634–641PubMedGoogle Scholar
  123. Schmid CL, Bohn LM (2010) Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a ß-arrestin2/Src/Akt signaling complex in vivo. J Neurosci official J Soc Neurosci 30:13513–13524Google Scholar
  124. 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 105:1079–1084PubMedPubMedCentralGoogle Scholar
  125. Schmid CL, Streicher JM, Meltzer HY, Bohn LM (2014) Clozapine acts as an agonist at serotonin 2A receptors to counter MK-801-induced behaviors through a betaarrestin2-independent activation of Akt. NeuropsychopharmacologyGoogle Scholar
  126. 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 78:544–553PubMedGoogle Scholar
  127. 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 20:8846–8852Google Scholar
  128. Sewell RA, Halpern JH, Pope HG Jr (2006) Response of cluster headache to psilocybin and LSD. Neurology 66:1920–1922PubMedGoogle Scholar
  129. Sheffler DJ, Kroeze WK, Garcia BG, Deutch AY, Hufeisen SJ, Leahy P, Bruning JC, Roth BL (2006) p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling. Proc Natl Acad Sci U S A 103:4717–4722PubMedPubMedCentralGoogle Scholar
  130. Shukla AK, Manglik A, Kruse AC, Xiao K, Reis RI, Tseng WC, Staus DP, Hilger D, Uysal S, Huang LY, Paduch M, Tripathi-Shukla P, Koide A, Koide S, Weis WI, Kossiakoff AA, Kobilka BK, Lefkowitz RJ (2013) Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497:137–141PubMedPubMedCentralGoogle Scholar
  131. Silbergeld EK, Hruska RE (1979) Lisuride and LSD: dopaminergic and serotonergic interactions in the “serotonin syndrome”. Psychopharmacology 65:233–237PubMedGoogle Scholar
  132. Singh RK, Dai Y, Staudinger JL, Muma NA (2009) Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907. Int J Neuropsychopharmacol 12:651–665PubMedGoogle Scholar
  133. Strange PG (1998) Three-state and two-state models. Trends Pharmacol Sci 19:85–86PubMedGoogle Scholar
  134. Svenningsson P, Tzavara ET, Carruthers R, Rachleff I, Wattler S, Nehls M, McKinzie DL, Fienberg AA, Nomikos GG, Greengard P (2003) Diverse psychotomimetics act through a common signaling pathway. Science (New York, N.Y.) 302:1412–1415PubMedGoogle Scholar
  135. Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P (2004) DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 44:269–296PubMedGoogle Scholar
  136. Tork I (1990) Anatomy of the serotonergic system. Ann N Y Acad Sci 600:9–34; discussion 34–35PubMedGoogle Scholar
  137. Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320:1–13Google Scholar
  138. 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 17:2785–2795Google Scholar
  139. 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 9:3897–3902Google Scholar
  140. Waeber C, Palacios JM (1994) Binding sites for 5-hydroxytryptamine-2 receptor agonists are predominantly located in striosomes in the human basal ganglia. Brain Res Mol Brain Res 24:199–209PubMedGoogle Scholar
  141. 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 104:7682–7687PubMedPubMedCentralGoogle Scholar
  142. 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 283:4387–4394PubMedGoogle Scholar
  143. Wu B, Chien EY, 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 330:1066–1071PubMedPubMedCentralGoogle Scholar
  144. Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (2012) Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485Google Scholar
  145. Wurmbach E, Yuen T, Ebersole BJ, Sealfon SC (2001) Gonadotropin-releasing hormone receptor-coupled gene network organization. J Biol Chem 276:47195–47201PubMedGoogle Scholar
  146. Xia Z (2003) The PDZ-binding domain is essential for the dendritic targeting of 5-HT2A serotonin receptors in cortical pyramidal neurons in vitro. Neuroscience 122:907–920PubMedGoogle Scholar
  147. 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 278:21901–21908PubMedGoogle Scholar
  148. Yuen T, Zhang W, Ebersole BJ, Sealfon SC (2002) Monitoring G-protein-coupled receptor signaling with DNA microarrays and real-time polymerase chain reaction. Methods Enzymol 345:556–569PubMedGoogle Scholar
  149. Yuen E, Jiang Q, Chen P, Feng J, Yan Z (2008) Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of NMDAR channels in pyramidal neurons of prefrontal cortex. J Biol ChemGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Juan F. López-Giménez
    • 1
  • Javier González-Maeso
    • 2
  1. 1.Instituto de Biomedicina y Biotecnología de Cantabria IBBTEC-CSICSantanderSpain
  2. 2.Department of Physiology and Biophysics, School of MedicineVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations