Skip to main content
SpringerLink
Log in

Serotonergic mechanisms in schizophrenia: Evolution and current concepts

  • Published:
Current Psychosis & Therapeutics Reports

Abstract

Serotonin (5-HT) was once thought to have a role in visual hallucinations based on the findings that lysergic acid diethylamide was found to be a serotonin agonist. This led to a search for endogenous indole hallucinogens in schizophrenia, which ultimately proved unsuccessful. Studies of 5-HT receptor subtypes opened up the issue in several ways, with the 5-HT2A, 5-HT2C, and 5-HT1A receptors seeming to be of greatest importance, and 5-HT6 and 5-HT7 receptors of secondary importance. Linkages between 5-HT, dopamine (DA), glutamate, acetylcholine, and brain-derived neurotrophic factor, have provided some important leads as to how 5-HT may be involved in schizophrenia. It has been found that 5-HT2A rather than 5-HT2C receptor stimulation is the most likely basis for the hallucinogenic effects of lysergic acid diethylamide, but recent neurochemical and genetic studies have raised the possibility that the 5-HT2C receptor may also be important in psychosis based on its ability to regulate tonic dopaminergic function. The discovery that 5-HT2A receptor blockade was an important component of the action of clozapine and other atypical antipsychotic drugs also restored interest in a primary role of 5-HT2A receptors in the etiology of psychosis. 5-HT1A receptors also have been found to enhance DA release in the cortex and hippocampus and are primary factor in the regulation of DA release in both of these regions. Postmortem studies have found some evidence of non-drug-induced increased density of 5-HT1A receptors. Genetic studies are ongoing to link single nucleotide polymorphisms of the 5-HT2A, 5-HT2C, and 5-HT1A receptors to some schizophrenia phenotypes. It is likely that serotonergic function will become even more important in developing genetic and other markers for schizophrenia novel therapies, particularly for psychosis and cognition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Gaddum JH:Serotonin-LSD interactions.Ann N Y Acad Sci 1957,66:643–647.

    Article  PubMed  CAS  Google Scholar 

  2. Glennon RA, Young R, Rosecrans JA:Antagonism of the effects of the hallucinogen DOM and the purported 5-HT agonist quipazine by 5-HT2 antagonists.Eur J Pharmacol 1983,91:189–196.

    Article  PubMed  CAS  Google Scholar 

  3. Berg KA, Clarke WP, Sailstad C, et al.:Signal transduction differences between 5-hydroxytryptamine type 2A and type 2C receptor systems.Mol Pharmacol 1994,46:477–484.

    PubMed  CAS  Google Scholar 

  4. Glennon RA, Titeler M, McKenney JD:Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents.Life Sci 1984,35:2505–2511.

    Article  PubMed  CAS  Google Scholar 

  5. Fiorella D, Helsley S, Rabin RA, Winter JC:The interactions of typical and atypical antipsychotics with the (-)2,5-dimethoxy-4-methamphetamine (DOM) discriminative stimulus.Neuropharmacol 1995,34:1297–1303.

    Article  CAS  Google Scholar 

  6. Arora RC, Meltzer HY:Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients.J of Neural Transmiss 1991,85:19–29.

    Article  CAS  Google Scholar 

  7. Burnet PW, Eastwood SL, Harrison PJ:5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia.Neuropsychopharmacology 1996,15:442–455.

    Article  PubMed  CAS  Google Scholar 

  8. Joyce JN, Shane A, Lexow N, et al.:Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics.Neuropsychopharmacology 1993,8:315–336.

    PubMed  CAS  Google Scholar 

  9. Trichard C, Paillere-Martinot ML, Attar-Levy D, et al.:No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET.Schizophrenia Res 1998,31:13–17.

    Article  CAS  Google Scholar 

  10. Umbricht D, Vollenweider FX, Schmid L, et al.:Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia.Neuropsychopharmacol 2003,28:170–181.

    Article  CAS  Google Scholar 

  11. Hasler F, Grimberg U, Benz MA, et al.:Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study.Psychopharmacol 2004,172:145–156.

    Article  CAS  Google Scholar 

  12. Gresch PJ, Smith RL, Barrett RJ, Sanders-Bush E:Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex.Neuropsychopharmacol 2005,30:1693–1702.

    Article  CAS  Google Scholar 

  13. Nichols CD, Garcia EE, Sanders-Bush E:Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration.Brain Res Mol Brain Res 2003,111:182–188.

    Article  PubMed  CAS  Google Scholar 

  14. Scruggs JL, Schmidt D, Deutch AY:The hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats.Neurosci Lett 2003,346:137–140.

    Article  PubMed  CAS  Google Scholar 

  15. Holmes C, Arranz MJ, Powell JF, et al.:5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer’s disease.Human Mol Genet 1998,7:1507–1509.

    Article  CAS  Google Scholar 

  16. Abdolmaleky HM, Faraone SV, Glatt SJ, Tsuang MT:Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia.Schiz Res 2004,67:53–62

    Article  Google Scholar 

  17. Masellis M, Basile V, Meltzer HY, et al.:Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients.Neuropsychopharmacol 1998,19:123–132.

    Article  CAS  Google Scholar 

  18. Castensson A, Emilsson L, Sundberg R, Jazin E:Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis.Biol Psychiatry 2003,54:1212–1221.

    Article  PubMed  CAS  Google Scholar 

  19. Castensson A, Aberg K, McCarthy S, et al.:Serotonin receptor 2C (HTR2C) and schizophrenia: examination of possible medication and genetic influences on expression levels.Am J Med Genet B Neuropsychiatr Genet 2005,134:84–89.

    PubMed  Google Scholar 

  20. Petronis A:The genes for major psychosis: aberrant sequence or regulation?.Neuropsychopharmacol 2000,23:1–12.

    Article  CAS  Google Scholar 

  21. Buckland PR, Hoogendoorn B, Guy CA, Smith SK, Coleman SL, O’Donovan MC:Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain.Am J Psychiatry 2005,162:613–615.

    Article  PubMed  Google Scholar 

  22. Meltzer HY:An atypical compound by any other name is still an atypical.Psychopharmacology 2000,148:16–19.

    Article  PubMed  CAS  Google Scholar 

  23. Meltzer HY, Matsubara S, Lee J-C:Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin 2 pKi values.J Pharmacol Exp Ther 1989,251:238–246.

    PubMed  CAS  Google Scholar 

  24. Meltzer HY, Nash JF:Effects of antipsychotic drugs on serotonin receptors.Pharmacol Rev 1991,43:587–604.

    PubMed  CAS  Google Scholar 

  25. Kane J, Honigfeld G, Singer J, et al.:Clozapine for the treatment resistant schizophrenic: A double blind comparison with chlorpromazine.Arch Gen Psychiatry 1988,45:789–796.

    PubMed  CAS  Google Scholar 

  26. Meltzer HY:Treatment-resistant schizophrenia — The role of clozapine.Curr Med Res Opinion 1997,14:1–20.

    Article  CAS  Google Scholar 

  27. Meltzer H, Alphs L, Green A, et al.:International Suicide Prevention Trial (InterSePT): reduced suicidality in schizophrenia with clozapine treatment.Arch Gen Psychiatry 2003,60:82–91.

    PubMed  CAS  Google Scholar 

  28. Meltzer HY, McGurk SR:The effect of clozapine, risperidone and olanzapine on cognitive function in schizophrenia.Schiz Bull 1999,25:233–255.

    CAS  Google Scholar 

  29. Woodward ND, Purdon SE, Meltzer HY, Zald DH:A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia.Int J Neuropsychopharm 2005,8:1–16.

    Article  CAS  Google Scholar 

  30. Meltzer HY:The role of serotonin in antipsychotic drug action.Neuropsychopharmacol 1999,21(Suppl 2):106S-115S.

    CAS  Google Scholar 

  31. Roth B, Craigo SC, Choudhary MS, Ulue A, Monsma FJ, Shen Y, Meltzer HY, Sibley DR:Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors.J Pharmacol Exp Ther 1994,268:1401–1410.

    Google Scholar 

  32. Meltzer HY, Fatemi S: The role of serotonin in schizophrenia and the mechanism of action of anti-psychotic drugs. InSerotonergic Mechanisms in Antipsychotic Treatment. Edited by Kane JM, Möller HJ, Awouters F. New York: Marcel Dekker; 1996:77–107.

    Google Scholar 

  33. Schotte A, Janssen PFM, Gommeren W, et al.:Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding.Psychopharmacol 1996,124:57–73.

    Article  CAS  Google Scholar 

  34. Protais P, Chagraoui A, Arbaoui J:Dopamine receptor antagonist properties of S 14506, 8-OH-DPAT, raclopride and clozapine in rodent.Eur J Pharmacol 1994,271:167–173.

    Article  PubMed  CAS  Google Scholar 

  35. Newman-Tancredi A, Gavaudan S, Conte C, et al.:Agonist and antagonist actions of antipsychotic agents at 5-HT1a receptors: a [35 S]GTPYS.Eur J Pharmacol 1998,355:245–256.

    Article  PubMed  CAS  Google Scholar 

  36. Roth BL, Meltzer HY: The role of serotonin in schizophrenia. InPsychopharmacology: The Fourth Generation. Edited by Bloom FE, Kupfer DJ. New York: Raven Press; 1995:1215–1227.

    Google Scholar 

  37. Kapur S, Remington G:Serotonin-dopamine interaction and its relevance to schizophrenia.Am J Psychiatry 1996,153:466–476.

    PubMed  CAS  Google Scholar 

  38. Martin P, Water N, Carlsson A, Carlsson ML:The apparent antipsychotic action of the 5-HT2a receptor antagonist M100907 in a mouse model of schizophrenia is counteracted by ritanserin.J Neural Transm 1997,104:561–564.

    Article  PubMed  CAS  Google Scholar 

  39. Marder SR:Risperidone in the treatment of schizophrenia.Am J Psychiatry 1994,151:825–835.

    PubMed  CAS  Google Scholar 

  40. Meltzer HY, Arvanitis L, Bauer D, Rein W:A placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder.Am J Psychiatry 2004,161:975–984.

    Article  PubMed  Google Scholar 

  41. Schmidt CJ, Sorensen SM, Kehne JH, et al.:The role of 5-HT2a receptors in antipsychotic activity.Life Sci 1995,56:2209–2222.

    Article  PubMed  CAS  Google Scholar 

  42. Gleason SC, Shannon HE.Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice.Psychopharmacol 1997,129:79–84.

    Article  CAS  Google Scholar 

  43. Varty GB, Higgins GA:Reversal of a dizocilpine-induced disruption of prepulse inhibition of an acoustic startle response by the 5-HT2 receptor antagonist katanserin.Eur J Pharmacol 1995,287:201–205.

    Article  PubMed  CAS  Google Scholar 

  44. Wadenberg ML, Hicks PB, Richter JT, et al.:Enhancement of antipsychotic like properties of raclopride in rats using the selective serotonin2A receptor antagonist MDL 100,907.Biol Psychiatr 1998,44:508–515.

    Article  CAS  Google Scholar 

  45. Ichikawa J, Meltzer HY:DOI, a 5-HT2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum.Brain Res 1995,698:204–208.

    Article  PubMed  CAS  Google Scholar 

  46. Carlsson ML, Martin P, Nilsson M, et al.:The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice.J Neural Transmiss (Budapest) 1999,106:123–129.

    Article  CAS  Google Scholar 

  47. Gleason SC, Shannon HE:Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice.Psychopharmacol 1997.129:79–84.

    Article  CAS  Google Scholar 

  48. Liegeois JF, Ichikawa J, Bonaccorso S, Meltzer HY:M100907, a 5-HT2A receptor antagonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex, but inhibits that in the nucleus accumbens.Neurosci Abs 2000,26:390.

    Google Scholar 

  49. Ichikawa J, Ishii H, Bonaccorso S, et al.:5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release.J Neurochem 2001,76:1521–3144.

    Article  PubMed  CAS  Google Scholar 

  50. Jakab RL, Goldman-Rakic P:5-Hydroxytryptamine 2a 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 1998,95:735–740.

    Article  PubMed  CAS  Google Scholar 

  51. Puig MV, Celada P, Artigas F:Serotonergic control of prefrontal cortex.Rev Neurol 2004,39:539–547.

    PubMed  CAS  Google Scholar 

  52. Buhot M-C:Serotonin receptors in cognitive behaviors.Curr Opin Neurobiol 1997,7:243–254.

    Article  PubMed  CAS  Google Scholar 

  53. Meneses A, Hong E:A pharmacological analysis of serotonergic receptors: effect of their activation of blockade in learning.Prog Neuropsychopharmacol Biol Psychiatry 1997,21:273–296.

    Article  PubMed  CAS  Google Scholar 

  54. Ruotsalainen S, Sirvio J, Jäkälä P, et al.:Differential effect of three 5-HT receptor antagonists on the performance of rats in attentional and working memory tasks.Eur Neuropsychopharmacol 1997,7:99–108.

    Article  PubMed  CAS  Google Scholar 

  55. Altman HJ, Stone WS, Ögren S:Evidence for a possible functional interaction between serotonergic and cholinergic mechanism in memory retrieval.Behav Neural Biol 1987,48:49–62.

    Article  PubMed  CAS  Google Scholar 

  56. Consolo S, Arnaboldi S, Giorgi S, et al.:5-HT4 receptor stimulation facilitates acetylcholine release in rat frontal cortex.Neuroreport 1994,5:1230–1232.

    PubMed  CAS  Google Scholar 

  57. Consolo S, Bertorelli R, Russi G, et al.:Serotonergic facilitation of acetylcholine release in vivo from rat dorsal hippocampus via serotonin 5-HT3 receptors.J Neurochem 1994,62:2254–2261.

    Article  PubMed  CAS  Google Scholar 

  58. Consolo S, Ramponi S, Ladinsky H, Baldi G:A critical role for D1 receptors in the 5-HT1A-mediated facilitation of in vivo acetylcholine release in rat frontal cortex.Brain Res 1996,707:320–323.

    Article  PubMed  CAS  Google Scholar 

  59. Sumiyoshi T, Matsui M, Yamashita I, et al.:Effect of adjunctive treatment with serotonin 1A agonist tandospirone on memory functions in schizophrenia.J Clin Psychopharmacol 2000,20:386–388.

    Article  PubMed  CAS  Google Scholar 

  60. Eaton MJ, Staley JK, Globus MY, Whittemore SR:Developmental regulation of early serotonergic neuronal differentiation: the role of brain-derived neurotrophic factor and membrane depolarization.Devel Biology 1995,170:169–182.

    Article  CAS  Google Scholar 

  61. Angelucci F, Brene S, Mathe AA.BDNF in schizophrenia, depression and corresponding animal models.Mol Psychiatry 2005,10:345–352.

    Article  PubMed  CAS  Google Scholar 

  62. Vaidya VA, Castro ME, Pei Q, et al.:Influence of thyroid hormone on 5-HT(1A) and 5-HT(2A) receptor-mediated regulation of hippocampal BDNF mRNA expression.Neuropharmacol 2001,40:48–56.

    Article  CAS  Google Scholar 

  63. Lang UE, Hellweg R, Gallinat I:Association of BDNT serum concentrations with central serotonergic activity: evidence from auditory signal processing.Neuropsychopharmacol 2005,30:1148–1153.

    Article  CAS  Google Scholar 

  64. Pazos A, Cortes R, Palacios JM.Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors.Brain Res 1985,346:231–249.

    Article  PubMed  CAS  Google Scholar 

  65. Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E:SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system.Neuropharmacol 1999,38:1195–1205.

    Article  Google Scholar 

  66. Lucas G, Spampinato:U Role of striatal serotonin 2A and serotonin 2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum.J Neurochem 2000,74:693–701.

    Article  PubMed  CAS  Google Scholar 

  67. Millan MJ, Dekeyne A, Gobert A.Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo.Neuropharmacology 1998,37:953–955.

    Article  PubMed  CAS  Google Scholar 

  68. Puig MV, Artigas F, Celada P:Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA.Cereb Cortex 2005,15:1–14.

    Article  PubMed  Google Scholar 

  69. Ichikawa J, Li Z, Dai J, Meltzer HY:Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor agonism.Brain Res 2002,956:349–357.

    Article  PubMed  CAS  Google Scholar 

  70. Millan MJ, Gobert A, Newman-Tancredi A, et al.:S16924 ((R)-2-{1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl}-1-(4-fluoro-phenyl)-ethanone), a novel potential antipsychotic with marked serotonin 5-HT1A agonist properties: 1. Receptorial and neurochemical profile in comparison with clozapine and haloperidol.J Pharmacol Exp Ther 1998,286:1341–1355.

    PubMed  CAS  Google Scholar 

  71. Huang YY, Battistuzzi C, Oquendo MA, et al.:Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology.Int J Neuropsychopharmacol 2004,7:441–451.

    Article  PubMed  CAS  Google Scholar 

  72. Sumiyoshi T, Stockmeier CA, Overholser JC, et al.:Serotonin 1A receptors are increased in postmortem prefrontal cortex in schizophrenia.Brain Research 1996,708:209–214.

    Article  PubMed  CAS  Google Scholar 

  73. Hashimoto T, Nishino N, Nakai H, Tanaka C:Increase in serotonin 5-HT1A receptors in prefrontal and temporal cortices of brains from patients with chronic schizophrenia.Life Sci 1991,48:355–363.

    Article  PubMed  CAS  Google Scholar 

  74. Mauler F, Fahrig T, Horvath E, Jork R.Inhibition of evoked glutamate release by the neuroprotective 5-HT(1A) receptor agonist BAY × 3702 in vitro and in vivo.Brain Res 2001,888:150–157.

    Article  PubMed  CAS  Google Scholar 

  75. Rollema H, Lu Y, Schmidt AW, Zorn SH:Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation.Eur J Pharmacol 1997,338:R3–5.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Vanderbilt University School of Medicine Psychiatric Hospital at Vanderbilt, 1601 23rd Avenue South, 37215, Nashville, TN, USA

    Herbert Y. Meltzer MD

Authors
  1. Herbert Y. Meltzer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhu Li PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mei Huang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adam Prus PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Herbert Y. Meltzer MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meltzer, H.Y., Li, Z., Huang, M. et al. Serotonergic mechanisms in schizophrenia: Evolution and current concepts. Current Psychosis & Therapeutics Reports 4, 12–19 (2006). https://doi.org/10.1007/BF02629409

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02629409

Keywords

Search

Navigation