Serotonin Receptors and Antipsychotic Drug Action

  • H. Y. Meltzer
Part of the Psychopharmacology Series book series (PSYCHOPHARM, volume 10)


The effect of serotonin (5-HT) to modulate dopaminergic activity in the nigrostriatal system has been known for some time (Dray et al. 1976). Generally, 5-HT has an inhibitory effect on dopaminergic output (see Meltzer and Nash 1991, for review). However, there is also evidence that 5-HT can enhance some aspects of dopaminergic function; thus, an over-simplistic one-way model should not be considered (Meltzer and Nash 1991). The effect of 5-HT in modulating dopaminergic activity is mediated via specific 5-HT receptors, the nature of which will be discussed subsequently. Due to the central role that antagonism of dopamine (DA) receptors has in the ability of antipsychotic drugs to reduce psychotic symptoms and in producing side effects such as extrapyramidal symptoms, tardive dyskinesia, and stimulation of prolactin secretion (Meltzer and Stahl 1976), it is necessary to consider whether serotonergic influences modulate the action of at least some antipsychotic drugs. As will be discussed, it has been suggested that serotonergic effects are particularly relevant to the action of clozapine and some other so-called atypical antipsychotic drugs (see Meltzer 1989; Deutch et al. 1991, for reviews). This article will consider the evidence for the action of antipsychotic drugs on specific 5-HT receptors as a contributing factor to their antipsychotic action or unique side effect profile.


Nucleus Accumbens Antipsychotic Drug Prolactin Secretion Dopaminergic Activity Atypical Antipsychotic Drug 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andree TH, Mikuni M, Tong CY, Koenig JI, Meltzer HY (1986) Differential effect of subchronic treatment with various neuroleptic agents on serotonin2 receptors in rat cerebral cortex. J Neurochem 46: 191–197PubMedCrossRefGoogle Scholar
  2. Ashby CR Jr, Edwards E, Harkius KL, Wang RY (1989) Differential effect of typical and atypical antipsychotic drugs on the suppressant action of 2-methylserotonin on medial prefrontal cortical cells: a micioiontophoretic study. Eur J Pharmacol 166: 583–584PubMedCrossRefGoogle Scholar
  3. Barnes JM, Barnes NM, Costall B, Ironside JW, Naylor RJ (1989) Identification and characterizations of 5-hydroxytryptamine3 recognition sites in human brain tissue. J Neurochem 53: 1787–1793PubMedCrossRefGoogle Scholar
  4. Bersani G, Grispini A, Marini S, Pasini A, Valducci M, Ciani N (1986) Neuroleptic-induced extrapyramidal side effects: clinical perspectives with ritanserin (R35667), a new selective 5-HT2 receptor blocking agent. Curr Ther Res 40: 492–499Google Scholar
  5. Blandina P, Goldfarb J, Craddock-Royal B, Green JP (1989) Release of endogenous dopamine by stimulation of 5-hydroxytryptamine receptors in rat striatum. J Pharmacol Exp Ther 251: 803–809PubMedGoogle Scholar
  6. Burki HR, Ruch W, Asper H (1975) Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat. Psychopharmacologia (Berl) 41: 27–33CrossRefGoogle Scholar
  7. Canton H, Verrièle L, Colpaert FC (1990) Binding of typical and atypical antipsychotics to 5-HT1c and 5-HT2 sites: clozapine potently interacts with 5-HTlc sites. Eur J Pharmacol 191: 93–96PubMedCrossRefGoogle Scholar
  8. Christensson E, Björk A (1990) Amperozide: a new pharmacological approach in the treatment of schizophrenia. Pharmacol Toxicol Suppl 1: 5–7CrossRefGoogle Scholar
  9. Costall B, Naylor R, Tyers M (1990) The psychopharmacology of 5-HT receptors. Pharmacol Ther 47: 181–202PubMedCrossRefGoogle Scholar
  10. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192: 481–483PubMedCrossRefGoogle Scholar
  11. Deutch AY, Moghaddam B, Innis RB, Krystal JH, Aghajanian GK, Bunney BS, Charney DS (1991) Mechanisms of action of atypical antipsychotic drugs. Implications for novel therapeutic strategies for schizophrenia. Schizophr Res 4: 121–156PubMedCrossRefGoogle Scholar
  12. Dray A, Gonye TJ, Oakley NR, Tanner T (1976) Evidence for the existance of a raphe projection to the substantia nigra in rat. Brain Res 113: 45–57PubMedCrossRefGoogle Scholar
  13. Drescher K, Hetey L (1988) Influence of antipsychotics and serotonin antagonists on presynaptic receptors modulating the release of serotonin in synaptosomes of the nucleus accumbens of rats. Neuropharmacology 27 (1): 31–36PubMedCrossRefGoogle Scholar
  14. Farde L, Wiesel FA, Nordstrom A-L, Sedvall G (1989) D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology (Berl) 99 Suppl:S-28–S-31Google Scholar
  15. Gerlach J, Behuke K, Heltberg J, Munk-Anderson E, Nielsen H (1985) Sulpiride and haloperidol in schizophrenia: a double-blind cross over study of therapeutic efficacy, side effects and plasma concentrations. Br J Psychiatry 147: 283–288PubMedCrossRefGoogle Scholar
  16. Gudelsky GA, Meltzer HY (1989) Activation of tuberoinfundibular dopamine neurons following the acute administration of atypical antipsychotics. Neuropsychopharmacology 2: 45–51PubMedCrossRefGoogle Scholar
  17. Harnryd C, Bjerkenstedt L, Bjork K, Gullberg B, Oxenstierna G, Sedvall G, Weisel F-A, Wik G, Aberg-Wistedt A (1984) Clinical evaluation of sulpiride in schizophrenic patients-a double-blind comparison with chlorpromazine. Acta Psychiatr Scand 69 Suppl 311: 7–20CrossRefGoogle Scholar
  18. Helmeste DM, Tang SW (1983) Unusual acute effects of antidepressants and neuroleptics on S2-serotonergic receptors. Life Sci 33: 2527–2533PubMedCrossRefGoogle Scholar
  19. Hoyer D (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Recept Res 8: 59–81PubMedGoogle Scholar
  20. Hoyer D, Gozlan H, Bolanos F, Schechter LE, Hamon M (1989) Interaction of psychotropic drugs with central 5-HT3 recognition sites: fact or artifact. Eur J Pharmacol 171: 137–139PubMedCrossRefGoogle Scholar
  21. Ichikawa J, Meltzer HY (1990) The effect of chronic clozapine and haloperidol on basal dopamine release and metabolism in rat striatum and nucleus accumbens studied by in vivo microdialysis. Eur J Pharmacol 176: 371–374PubMedCrossRefGoogle Scholar
  22. Ichikawa J, Meltzer HY (1991) Differential effects of repeated treatment with haloperidol and clozapine on dopamine release and metabolism in the striatum and nucleus accumbens. J Pharmacol Exp Ther 256: 348–357PubMedGoogle Scholar
  23. Imperato A, Angelucci L (1989) 5-HT3 receptors control dopamine release in the nucleus accumbens of freely moving rats. Neurosci Lett 101:214–217PubMedCrossRefGoogle Scholar
  24. Julius D, Macdermott AB, Axe R, Jessell TM (1988) Molecular characterization of a functional cDNA encoding the serotonin1C receptor. Science 241: 558–564PubMedCrossRefGoogle Scholar
  25. Julius D, Livelli TJ, Jessell TM, Axel R (1989) Ectopic expression of the serotonin1c receptor and the triggering of malignant transformation. Science 244: 1057–1062PubMedCrossRefGoogle Scholar
  26. Kane J, Honigfeld G, Singer J, Meltzer HY (1988) Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry 45: 789–796PubMedGoogle Scholar
  27. Köhler C, Hall H, Magnusson O, Lewander T, Gustafsson K (1990) Biochemical pharmacology of the atypical neuroleptic remoxipride. Acta Psychiatr Scand 82 Suppl 358: 27–36CrossRefGoogle Scholar
  28. Lewander T, Westerberg S-E, Morrison D (1990) Clinical profile of remoxipride - a combined analysis of a comparative double-blind multicenter trial programme. Acta Psychiatr Scand 82 Suppl 358: 92–98CrossRefGoogle Scholar
  29. Maj J, Sowinska H, Baran L, Palider W (1974) The central action of clozapine. Pol J Pharmacol Pharm 26: 425–435PubMedGoogle Scholar
  30. Mann JJ, Bartles M, Bauer H, Gaertner HJ (1984) Amisulpride-an open clinical study of a new benzamide in schizophrenic patients. Pharmacopsychiatry 17: 111–115PubMedCrossRefGoogle Scholar
  31. Matsubara S, Meltzer HY (1989) Effect of typical and atypical antipsychotic drugs on 5- HT2 receptor density in rat cerebral cortex. Life Sci 45: 1397–1406PubMedCrossRefGoogle Scholar
  32. McKenna DJ, Nazarali AJ, Hoffman AJ, Nichols DE, Mathis CA, Saavedra JM (1989) Common receptors for hallucinogens in rat brain: a comparative autoradiographic study using [125I]LSD and [125I]DOI, a new psychotomimetic radioligand. Brain Res 476: 45–56PubMedCrossRefGoogle Scholar
  33. Meltzer HY (1988) Clozapine: clinical advantages and biological mechanisms. In: Schulz C, Tamminga C (eds) Schizophrenia: a scientific focus. International conference on schizophrenia. Oxford University Press, New York, pp 302–309Google Scholar
  34. Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99: S18–S27CrossRefGoogle Scholar
  35. Meltzer HY (1990a) Clozapine: mechanism of action in relation to its clinical advantages. In: Kales A, Stefanos GN, Talbott J A (eds) Recent advances in schizophrenia. Springer, Berlin Heidelber New York, pp 237–246CrossRefGoogle Scholar
  36. Meltzer HY (1990b) The role of serotonin in the action of atypical antipsychotic drugs. Psychiatr Ann 20 (10): 571–579Google Scholar
  37. Meltzer HY (1991) The mechanism of action of novel antipsychotic drugs. Schizophr Bull 17: 263–287PubMedGoogle Scholar
  38. Meltzer HY, Nash JF (1991) The effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43: 587–604PubMedGoogle Scholar
  39. Meltzer HY, Stahl SM (1976) The dopamine hypothesis of schizophrenia: a review. Schizophr Bull 2 (1): 19–76PubMedGoogle Scholar
  40. Meltzer HY, Stockmeier CA (1992) The influence of 5-HT2/5-HT1c receptor blockade on the action of clozapine and other Type A atypical antipsychotic drugs. Br J Psychiatry (in press)Google Scholar
  41. Meltzer HY, Daniels S, Fang VS (1975) Clozapine increases rat serum prolactin levels. Life Sci 17: 339–342PubMedCrossRefGoogle Scholar
  42. Meltzer HY, Young M, Metz J, Fang VS, Schyve PM, Arora RC (1985) Extrapyramidal side effects and increased serum prolactin following fluoxetine, a new antidepressant. J Neural Transm 45: 165–175CrossRefGoogle Scholar
  43. Meltzer HY, Sommers A A, Luchins DJ (1986) The effect of neuroleptics and other psychotropic drugs on negative symptoms in schizophrenia. J Clin Psychopharmacol 6: 329–338PubMedCrossRefGoogle Scholar
  44. Meltzer HY, Alphs LD, Bastani B, Ramirez L (1989a) Effect of melperone in treatment resistant schizophrenia (Abstr). Excerpta Med Int Congr Ser 889: 502Google Scholar
  45. Meltzer HY, Bastani B, Kwon KY, Ramirez L, Burnett S, Sharpe J (1989b) A prospective study of clozapine in treatment resistant schizophrenic patients. I. Preliminary report. Psychopharmacology (Berl) 99 Suppl:S68–S72CrossRefGoogle Scholar
  46. Meltzer HY, Matsubara S, Lee J-C (1989c) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1? D2 and serotonin2 pKi values. J Pharmacol Exp Ther 251: 238–246PubMedGoogle Scholar
  47. Meltzer HY, Zhang Y, Stockmeier CA (1990) Effect of typical and atypical antipsychotic drugs (APD) on frontal cortical (FC), serotonin2 (5-HT2) and striatal (STR) dopamine2 (DA2) binding in vivo. Neurosci Abstr 16: 586Google Scholar
  48. Mertens C, Dewilds J, Dierick M, Bergman I, Gustavsson G (1989) Clinical trials of amperozide in schizophrenia (Abstr). Excerpta Med Int Congr Ser 889: 502Google Scholar
  49. Miller RJ, Hiley CR (1974) Anti-muscarinic properties of neuroleptics and drug-induced parkinsonism. Nature 248: 596–597PubMedCrossRefGoogle Scholar
  50. Molineaux SM, Jessell TM, Axel R, Julius D (1989) 5-HT1c receptor is a prominent serotonin receptor subtype in the central nervous system. Proc Natl Acad Sci USA 86:6793–6797PubMedCrossRefGoogle Scholar
  51. Nash JF, Meltzer HY, Gudelsky GA (1988) Antagonism of serotonin receptor mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat. Eur J Pharmacol 151: 463–469PubMedCrossRefGoogle Scholar
  52. Palacios JM, Waeber C, Hoyer D, Mengod G (1990) Distribution of serotonin receptors. The neuropharmacology of serotonin. Ann NY Acad Sci 600: 36–52PubMedCrossRefGoogle Scholar
  53. Pazos A, Hoyer D, Palacios J (1984) The binding of serotonergic ligands to the porcine choroid plexus: characterization of an new type of serotonin recognition site. Eur J Pharmacol 106: 539–546PubMedCrossRefGoogle Scholar
  54. Pazos A, Cortes R, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346: 231–249PubMedCrossRefGoogle Scholar
  55. Reyntjens A, Gelders YG, Hoppenbrouwers M-L, Vanden Bussche G (1986) Thymosthenic effects of ritanserin (R 55667), a centrally acting serotonin-S2 blocker. Drug Dev Res 8: 205–211CrossRefGoogle Scholar
  56. Ruch W, Asper H, Burki HR (1976) Effect of clozapine on the metabolism of serotonin in rat brain. Psychopharmacologia (Berl) 46: 103–109CrossRefGoogle Scholar
  57. Schmidt AW, Peroutka SJ (1989) 5-Hydroxytryptamine receptor ‘families’. FASEB J 3:2242–2249PubMedGoogle Scholar
  58. Seeman P, Chau-Wong M, Tedesco J, Wong K (1975) Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci USA 72: 4376–4380PubMedCrossRefGoogle Scholar
  59. Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347: 146–151PubMedCrossRefGoogle Scholar
  60. Sunahara RK, Guan H-C, O’Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HHM, Niznik HB (1991) Cloning of the gene for a human dopamine 5 receptor with higher affinity for dopamine than D1. Nature 350: 614–619PubMedCrossRefGoogle Scholar
  61. Svartengren J, Simonsson P (1990) Receptor binding properties of amperozide. Pharmacol Toxicol Suppl 1: 8–11CrossRefGoogle Scholar
  62. Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350: 610–614PubMedCrossRefGoogle Scholar
  63. Wander TJ, Nelson A, Okazaki H, Richelson E (1987) Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2 receptors of normal human brain in vitro. Eur J Pharmacol 143: 279–282PubMedCrossRefGoogle Scholar
  64. Watling KJ, Beer MS, Stanton J A, Newberry NR (1990) Interaction of the atypical neuroleptic clozapine with 5-HT3 receptors in the cerebral cortex and superior ganglion of the rat. Eur J Pharmacol 182: 465–472PubMedCrossRefGoogle Scholar
  65. Yagaloff KA, Hartig GR (1985) 125I-lysergic acid diethylamide binds to a novel serotonergic site on rat choroid plexus epithelial alls. J Neurosci 5:3718–3183Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • H. Y. Meltzer
    • 1
  1. 1.Departments of Psychiatry and PharmacologyCase Western Reserve University School of MedicineClevelandUSA

Personalised recommendations