Abstract
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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
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: 191–197
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: 583–584
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: 1787–1793
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: 492–499
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: 803–809
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: 27–33
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: 93–96
Christensson E, Björk A (1990) Amperozide: a new pharmacological approach in the treatment of schizophrenia. Pharmacol Toxicol Suppl 1: 5–7
Costall B, Naylor R, Tyers M (1990) The psychopharmacology of 5-HT receptors. Pharmacol Ther 47: 181–202
Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192: 481–483
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: 121–156
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: 45–57
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): 31–36
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-31
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: 283–288
Gudelsky GA, Meltzer HY (1989) Activation of tuberoinfundibular dopamine neurons following the acute administration of atypical antipsychotics. Neuropsychopharmacology 2: 45–51
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: 7–20
Helmeste DM, Tang SW (1983) Unusual acute effects of antidepressants and neuroleptics on S2-serotonergic receptors. Life Sci 33: 2527–2533
Hoyer D (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Recept Res 8: 59–81
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: 137–139
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: 371–374
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: 348–357
Imperato A, Angelucci L (1989) 5-HT3 receptors control dopamine release in the nucleus accumbens of freely moving rats. Neurosci Lett 101:214–217
Julius D, Macdermott AB, Axe R, Jessell TM (1988) Molecular characterization of a functional cDNA encoding the serotonin1C receptor. Science 241: 558–564
Julius D, Livelli TJ, Jessell TM, Axel R (1989) Ectopic expression of the serotonin1c receptor and the triggering of malignant transformation. Science 244: 1057–1062
Kane J, Honigfeld G, Singer J, Meltzer HY (1988) Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry 45: 789–796
Köhler C, Hall H, Magnusson O, Lewander T, Gustafsson K (1990) Biochemical pharmacology of the atypical neuroleptic remoxipride. Acta Psychiatr Scand 82 Suppl 358: 27–36
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: 92–98
Maj J, Sowinska H, Baran L, Palider W (1974) The central action of clozapine. Pol J Pharmacol Pharm 26: 425–435
Mann JJ, Bartles M, Bauer H, Gaertner HJ (1984) Amisulpride-an open clinical study of a new benzamide in schizophrenic patients. Pharmacopsychiatry 17: 111–115
Matsubara S, Meltzer HY (1989) Effect of typical and atypical antipsychotic drugs on 5- HT2 receptor density in rat cerebral cortex. Life Sci 45: 1397–1406
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: 45–56
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 302–309
Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99: S18–S27
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 237–246
Meltzer HY (1990b) The role of serotonin in the action of atypical antipsychotic drugs. Psychiatr Ann 20 (10): 571–579
Meltzer HY (1991) The mechanism of action of novel antipsychotic drugs. Schizophr Bull 17: 263–287
Meltzer HY, Nash JF (1991) The effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43: 587–604
Meltzer HY, Stahl SM (1976) The dopamine hypothesis of schizophrenia: a review. Schizophr Bull 2 (1): 19–76
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)
Meltzer HY, Daniels S, Fang VS (1975) Clozapine increases rat serum prolactin levels. Life Sci 17: 339–342
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: 165–175
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: 329–338
Meltzer HY, Alphs LD, Bastani B, Ramirez L (1989a) Effect of melperone in treatment resistant schizophrenia (Abstr). Excerpta Med Int Congr Ser 889: 502
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–S72
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: 238–246
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: 586
Mertens C, Dewilds J, Dierick M, Bergman I, Gustavsson G (1989) Clinical trials of amperozide in schizophrenia (Abstr). Excerpta Med Int Congr Ser 889: 502
Miller RJ, Hiley CR (1974) Anti-muscarinic properties of neuroleptics and drug-induced parkinsonism. Nature 248: 596–597
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 86:6793–6797
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: 463–469
Palacios JM, Waeber C, Hoyer D, Mengod G (1990) Distribution of serotonin receptors. The neuropharmacology of serotonin. Ann NY Acad Sci 600: 36–52
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: 539–546
Pazos A, Cortes R, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346: 231–249
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: 205–211
Ruch W, Asper H, Burki HR (1976) Effect of clozapine on the metabolism of serotonin in rat brain. Psychopharmacologia (Berl) 46: 103–109
Schmidt AW, Peroutka SJ (1989) 5-Hydroxytryptamine receptor ‘families’. FASEB J 3:2242–2249
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: 4376–4380
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: 146–151
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: 614–619
Svartengren J, Simonsson P (1990) Receptor binding properties of amperozide. Pharmacol Toxicol Suppl 1: 8–11
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: 610–614
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: 279–282
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: 465–472
Yagaloff KA, Hartig GR (1985) 125I-lysergic acid diethylamide binds to a novel serotonergic site on rat choroid plexus epithelial alls. J Neurosci 5:3718–3183
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Meltzer, H.Y. (1993). Serotonin Receptors and Antipsychotic Drug Action. In: Gram, L.F., Balant, L.P., Meltzer, H.Y., Dahl, S.G. (eds) Clinical Pharmacology in Psychiatry. Psychopharmacology Series, vol 10. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-78010-3_7
Download citation
DOI: https://doi.org/10.1007/978-3-642-78010-3_7
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-78012-7
Online ISBN: 978-3-642-78010-3
eBook Packages: Springer Book Archive