Skip to main content
Log in

Interactions between 5-HT3 receptors and cerebral dopamine function: implications for the treatment of schizophrenia and psychoactive substance abuse

  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

This article reviews current knowledge on the interaction between 5-hydroxytryptamine (5-HT), acting at 5-HT3 receptors in the CNS, and cerebral dopamine systems. Since 1987, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies has demonstrated a clear role for 5-HT3 receptors in the modulation of activity of mesolimbic and mesocortical dopamine neurones. This evidence has led to the suggestion that 5-HT3 receptor antagonists have potential as novel antipsychotic agents and may also find use in the treatment of psychoactive substance abuse. Data emerging from clinical studies generally support this hypothesis and suggest that 5-HT3 antagonists may prove to be among the first agents available to treat schizophrenia which are not dopamine D2 antagonists and hence lack their side-effect problems.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Abi-Dargham A, Laruelle M, Wong DT, Robertson DW, Weinberger DR, Kleinman JE (1991) 5-HT3 receptors in postmortem brains of normal and schizophrenic subjects. Soc Neurosci Abstr 287.11

  • Ashby CR, Edwards E, Harkins K, Wang RY (1989) Characterization of 5-HT3 receptors in the medial prefrontal cortex: a microinotophoretic study. Eur J Pharmacol 173:193–196

    Article  PubMed  Google Scholar 

  • Ashby CR, Edwards E, Minabe Y, Wang RY (1990) Functional characterization of 5-HT3-like receptors in the rat medial prefrontal cortex: biochemical and electrophysiological studies. Eur J Pharmacol 183:1958–1959

    Article  Google Scholar 

  • Ashby CR, Minabe Y, Edwards E, Wang R (1991) 5-HT3-like receptors in the rat medial prefrontal cortex: an electrophysiological study. Brain Res 550:181–191

    Article  PubMed  Google Scholar 

  • Barnes JM, Barnes NM, Costall B, Ironside JW, Naylor RJ (1989) Identification and characterisation of 5-HT3 recognition sites in human brain tissue. J Neurochem 53:1787–1793

    PubMed  Google Scholar 

  • Barnes JM, Barnes NM, Champaneria S, Costall B, Naylor RJ (1990) Characterization and autoradiographic localization of 5-HT3 receptor recognition sites identified with [3H]-(S)-zaco-pride. Neuropharmacology 29:1037–1045

    Article  PubMed  Google Scholar 

  • Baruch I, Hemsley DR, Gray JA (1988) Differential performance of acute and chronic schizophrenics in a latent inhibition task. J Nerv Ment Dis 176:598–606

    PubMed  Google Scholar 

  • Bilsky EJ, Reid LD (1991) MDL72222, a serotonin 5-HT3 receptor antagonist, blocks MDMA's ability to establish a conditioned place preference. Pharmacol Biochem Behav 39:509–512

    Article  PubMed  Google Scholar 

  • Blandina P, Goldfarb J, Green JP (1988) Activation of a 5-HT3 receptor release dopamine from rat striatal slice. Eur J Pharmacol 155:349–350

    Article  PubMed  Google Scholar 

  • Bozarth MA, Wise RA (1986) Involvement of the ventral tegmental dopamine system in opioid and psychomotor stimulant reinforcement. Natl Inst Drug Abuse Res Monogr Ser 67:190–196

    Google Scholar 

  • Bunce KT, Tyers MB, Beranek P (1991) Clinical evaluation of 5-HT3 receptor antagonists as anti-emetics. TIPS 12:46–48

    PubMed  Google Scholar 

  • Butler A, Hill JM, Ireland SJ, Jordan CC, Tyers MB (1988) Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors. Br J Pharmacol 94:397–412

    PubMed  Google Scholar 

  • Carboni E, Acquas E, Leone P, Perezzani L, Di Chiara G (1988) 5-HT3 receptor antagonists block morphine- and nicotine-induced place preference conditioning. Eur J Pharmacol 151:159–160

    Article  PubMed  Google Scholar 

  • Carboni E, Acquas E, Leone P, Di Chiara G (1989a) 5-HT3 receptor antagonists block morphine- and nicotine- but not amphetamine-induced reward. Psychopharmacology 97:175–178

    Article  PubMed  Google Scholar 

  • Carboni E, Acquas E, Frau R, Di Chiara G (1989b) Differential inhibitory effects of a 5-HT3 antagonist on drug-induced stimulation of dopamine release. Eur J Pharmacol 164:515–519

    Article  PubMed  Google Scholar 

  • Chen J, van Praag HM, Gardner EL (1991) Activation of 5-HT3 receptor by 1-phenylbiguanide increases dopamine release in the rat nucleus accumbens. Brain Res 543:354–357

    Article  PubMed  Google Scholar 

  • Chen J, Paredes W, van Praag HM, Lowinson J, Gardner EL (1992) Presynaptic dopamine release is enhanced by 5-HT3 receptor activation in medial prefrontal cortex of freely moving rats. Synapse 10:264–266

    Article  PubMed  Google Scholar 

  • Christoffersen CL, Serpa KA, Meltzer LT (1988) Effects of the serotonin-3 (5-HT3) antagonist, GR38032F, on midbrain dopamine (DA) neurons. Soc Neurosci Abstr 14:339.13

    Google Scholar 

  • Costall B, Domeney AM, Naylor RJ (1984) Long term consequences of neuroleptic antagonism of behavioural events occurring during mesolimbic dopamine infusion. Neuropharmacology 24:287–294

    Article  Google Scholar 

  • Costall B, Domeney AM, Naylor RJ, Tyers MB (1987a) Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of rat and marmoset brain. Br J Pharmacol 92:881–894

    PubMed  Google Scholar 

  • Costall B, Domeney AM, Kelly ME, Naylor RJ, Tyers MB (1987b) Antipsychotic potential of GR38032F, a selective antagonist of 5-HT3 receptors in the central nervous system. Br J Pharmacol 90:89P

  • Costall B, Jones BJ, Kelly ME, Naylor R, Oakley NR, Onaivi ES, Tyers MB (1989) The effects of ondansetron (GR38032F) in rats and mice treated subchronically with diazepam. Pharmacol Biochem Behav 34:769–778

    Article  PubMed  Google Scholar 

  • Costall B, Domeney AM, Naylor RJ (1990a) 5-HT3 receptor antagonists attenuate dopamine-induced hyperactivity in the rat. Neuroreport 1:77–80

    PubMed  Google Scholar 

  • Costall B, Naylor RJ, Tyers MB (1990b) The psychopharmacology of 5-HT3 receptors. Pharmacol Ther 47:181–202

    Article  PubMed  Google Scholar 

  • Costall B, Jones BJ, Kelly ME, Naylor RJ, Onaivi ES, Tyers MB (1990c) Ondansetron inhibits a behavioural consequence of withdrawing from drugs of abuse. Pharmacol Biochem Behav 36:339–344

    Google Scholar 

  • Crook TH, Lakin M (1991) Effects of ondansetron in age-associated memory impairment. The role of ondansetron, a novel 5-HT3 antagonist, in the treatment of psychiatric disorders. Satellite Symposium of 5th World Congress of Biological Psychiatry, Fiorence, Italy

  • Derkach V, Surprenant A, North RA (1989) 5-HT3 receptor are membrane ion channels. Nature 339:706–709

    Article  PubMed  Google Scholar 

  • Deveaugh-Geiss J, McBain S, Bell JM, Williams P, Corn T (1990) The effect of a novel 5-HT3 antagonist, ondansetron, in schizophrenia: results from uncontrolled trials. ANCP Satellite Conference, San Juan, Puerto Rico, Conference Proceedings

  • Eison AS, Eison MS, Iversen SD (1982) The behavioural effects of a novel substance P analogue following infusion into the ventral tegmental area or substantia nigra of rat brain. Brain Res 238:137–152

    Article  PubMed  Google Scholar 

  • Ellenbroek BA, Cools AR (1990) Animal models with construct validity for schizophrenia. Behav Pharmacol 1:469–490

    PubMed  Google Scholar 

  • Fadda F, Garau B, Marchel F, Colombo G, Gessa GL (1991) MDL 72222, a selective 5-HT3 receptor antagonist, suppresses voluntary ethanol consumption in alcohol-preferring rats. Alcohol Alcohol 26:107–110

    PubMed  Google Scholar 

  • Fastier FN (1962) Structure-activity relationships of amidine derivatives. Pharmacol Rev 14:37–90

    PubMed  Google Scholar 

  • Fozard JR (1984) MDL72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn-Schmiedeberg's Arch Pharmacol 326:36–44

    Article  Google Scholar 

  • Goudie AJ, Leathley MJ (1990) Effects of the 5-HT3 antagonist (ondansetron) on benzodiazepine withdrawal in rats. Eur J Pharmacol 185:179–186

    Article  PubMed  Google Scholar 

  • Grant KA, Barrett JE (1991) Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists. Psychopharmacology 104:451–456

    PubMed  Google Scholar 

  • Hagan RM, Butler, A, Hill JM, Jordan CC, Ireland SJ, Tyers MB (1987) Effect of the 5-HT3 receptor antagonist, GR38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of rat brain. Eur J Pharmacol 138:303–305

    Article  PubMed  Google Scholar 

  • Hagan RM, Jones BJ, Jordan CC, Tyers MB (1990) Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in rat. Br J Pharmacol 99:227–232

    PubMed  Google Scholar 

  • Hagan RM, Oakley NR, Burridge GJ, Kilaptrick GJ, Tyers MB (1991) Effects of the 5-HT3 receptor antagonist, GR68755, in models of anxiety and raised mesolimbic dopaminergic activity in the rat. In: Serotonin 1991. 5-Hydroxytryptamine — CNS receptors and brain function. Birmingham, UK, p 115

  • Higgins GA, Nguyen P, Joharchi N, Sellers EM (1991) Effects of 5-HT3 receptor antagonists on behavioural measures of naloxone-precipitated opioid withdrawal. Psychopharmacology 105:322–328

    Article  PubMed  Google Scholar 

  • Higgins GA, Nguyen P, Joharchi N, Sellers EM (1992) Effect of the 5-HT3 antagonists, MDL72222 and ondansetron, on morphine place conditioning. Psychopharmacology 106:315–320

    PubMed  Google Scholar 

  • Ireland SJ, Tyers MB (1987) Pharmacological characterization of 5-hydroxytryptamine-induced depolarization of the rat isolated vagus nerve. Br J Pharmacol 90:229–238

    PubMed  Google Scholar 

  • Imperato A, Angelucci L (1989) 5-HT3 receptors control dopamine release in the nucleus accumbens of freely moving rats. Neurosci Lett 101:214–217

    Article  PubMed  Google Scholar 

  • Imperato A, Puglisi-Allergra S, Zocchi A, Scrocco MG, Casolini P, Angelucci L (1990) Stress activation of limbic and cortical dopamine release is prevented by ICS205-930 but not diazepam. Eur J Pharmacol 175:211–214

    Article  PubMed  Google Scholar 

  • Jackson DM, Chieng B, Gillies DM, Mylecharane EJ (1991) 5-Hydroxytryptamine (5-HT) receptors and hyperlocomotion in rodents. Soc Neurosci Abstr 239:3

    Google Scholar 

  • Jasinski DR, Preston KL, Testa M, Sullivan JT (1991) Evaluation of the 5-HT3 antagonist ondansetron for cocaine-like activity and abuse potential. NIDA Res Monogr 105:515

    PubMed  Google Scholar 

  • Jiang LH, Ashby CR Jr, Kasser RJ, Wang RY (1990) The effect of intraventricular administration of the 5-HT3 receptor agonist 2-methylserotonin on the release of dopamine in the nucleus accumbens: an in vivo chronocoulometric study. Brain Res 513:156–160

    Article  PubMed  Google Scholar 

  • Jones BJ, Costall B, Domeney AM, Kelly ME, Naylor RJ, Oakley NR, Tyers MB (1988) The potential anxiolytic activity of GR38032F, a 5-HT3 receptor antagonist. Br J Pharmacol 93:985–993

    PubMed  Google Scholar 

  • Kennett GA, Blackburn TP (1991) Inhibition of agonist-induced dopamine release in the rat nucleus accumbens by BRL 46470, an in vivo dialysis study. In: Serotonin 1991. 5-Hydroxytrypta-mine-CNS receptors and brain function. Birmingham, UK, p 73

  • Kilpatrick GJ, Jones BJ, Tyers MB (1987) Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 330:746–748

    Article  PubMed  Google Scholar 

  • Kilpatrick GJ, Jones BJ, Tyers MB (1988) The distribution of specific binding of the 5-HT3 receptor ligand [3H] GR65630 in rat brain using quantitative autoradiography. Neurosci Lett 94:156–160

    Article  PubMed  Google Scholar 

  • Kilpatrick GJ, Jones BJ, Tyers MB (1989) Binding of the 5-HT3 ligand, [3H]GR65630 to rat area postrema, vagus nerve and the brains of several species. Eur J Pharmacol 159:157–164

    Article  PubMed  Google Scholar 

  • Kilpatrick GJ, Bunce KT, Tyers MB (1990a) 5-HT3 receptors. Med Res Rev 10:441–475

    PubMed  Google Scholar 

  • Kilpatrick GJ, Butler A, Burridge J, Oxford AW (1990b) 1-(m-Chlorophenyl)-biguanide, a potent high affinity 5-HT3 receptor agonist. Eur J Pharmacol 182:193–197

    Article  PubMed  Google Scholar 

  • Kilpatrick GJ, Hagan RM, Butler A, Burridge J, North PC, Oxford A, Tyers MB (1991) GR68755, a potent and selective antagonist at 5-HT3 receptors. Br J Pharmacol 104:259P

  • Koob GF, Bloom FE (1988) Cellular and molecular mechanisms of drug dependence. Science 242:715–722

    PubMed  Google Scholar 

  • Lader MH (1991) Ondansetron in the treatment of anxiety. The role of ondansetron, a novel 5-HT3 antagonist, in the treatment of psychiatric disorders. Satellite Symposium of 5th World Congress of Biological Psychiatry, Florence, Italy

  • Lane JD, Pickering CL, Hooper ML, Fagan K, Tyers MB, Emmett-Oglesby MW (1992) Failure of ondansetron to block the discriminative or reinforcing stimulus properties of cocaine in the rat. Drug Alcohol Depend 30:151–162

    Article  PubMed  Google Scholar 

  • Leeser J, Lip H (1991) Prevention of postoperative nausea and vomiting using ondansetron, a new, selective, 5-HT3 receptor antagonist. Anesth Analg 72:751–755

    PubMed  Google Scholar 

  • Lovinger DM (1991) Ethanol potentiation of 5-HT3 receptor mediated ion current in NCB-20 neuroblastoma cells. Neurosci Lett 122:57–60

    Article  PubMed  Google Scholar 

  • McBain, SL, Dineen M, Weller M, Taylor S, Cooksey P, Williams P, Corn T (1992) Ondansetron. A double blind placebo controlled study in acute schizophrenia. Schizophr Res 6:112

    Article  Google Scholar 

  • Maricq AV, Peterson AS, Brake AJ, Myers RM and Julius D (1991) Primary structure and functional expression of the 5-HT3 receptor, a serotonin-gated ion channel. Science 254:432–437

    PubMed  Google Scholar 

  • Minabe Y, Ashby CR, Wang RY (1992) Effects produced by acute and chronic treatment with granisetron alone or in combination with haloperidol on midbrain dopamine neurons. Eur Neuropsychopharmacol 2:127–133

    Article  PubMed  Google Scholar 

  • Moser PC (1990) Inhibition of nicotine-induced hyperactivity by a 5-HT3 receptor antagonist. Eur J Pharmacol 183:1950

    Article  Google Scholar 

  • Moser PC (1992) The effect of 5-HT3 receptor antagonists on the discriminative stimulus effects of amphetamine. Eur J Pharmacol 212:271–274

    Article  PubMed  Google Scholar 

  • Oakley NR, Jones BJ, Tyers MB, Costall B, Domeney AM (1988a) The effect of GR38032F on alcohol consumption in the marmoset. Br J Pharmacol 96:870P

    Google Scholar 

  • Oakley NR, Jones BJ, Tyers MB (1988b) Tolerance and withdrawal studies with diazepam and GR38032F in the rat. Br J Pharmacol 95:764P

    Google Scholar 

  • Paris JM, Cunningham KA (1991) Serotonin 5-HT3 antagonists do not alter the discriminative stimulus properties of cocaine. Psychopharmacology 104:475–478

    Article  PubMed  Google Scholar 

  • Paudice P, Raiteri M (1991) Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens. Br J Pharmacol 103:1790–1794

    PubMed  Google Scholar 

  • Peltier R, Schenk S (1991) GR38032F, a serotonin 5-HT3 antagonist, fails to alter cocaine self-administration in rats. Pharmacol Biochem Behav 39:133–136

    Article  PubMed  Google Scholar 

  • Perry DC (1990) Autoradiography of [3H]quipazine in rodent brain. Eur J Pharmacol 187:75–85

    Article  PubMed  Google Scholar 

  • Pratt GD, Bowery NG, Kilpatrick GJ, Leslie RA, Barnes NM, Naylor RJ, Jones BJ, Nelson DR, Palacios JM, Slater P, Reynolds DJM (1990) Consensus meeting agrees distribution of 5-HT3 receptors in mammalian hindbrain. TIPS 1:135–137

    Google Scholar 

  • Ramaswamy S, Bapna JS (1986) Antagonism of morphine tolerance and dependence by metoclopramide. Life Sci 40:807–810

    Article  Google Scholar 

  • Reith MEA (1990) 5-HT3 antagonists attenuate cocaine-induced locomotion in mice. Eur J Pharmacol 186:327–330

    Article  PubMed  Google Scholar 

  • Richardson BP, Engel G, Donatsch P, Stadler PA (1985) Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 316:126

    Article  PubMed  Google Scholar 

  • Sanger GJ, Nelson DR (1989) Selective and functional 5-hydroxy-tryptamine3 receptor antagonism by BRL 43694 (granisetron). Eur J Pharmacol 159:113–124

    Article  PubMed  Google Scholar 

  • Schmidt CJ, Black CK (1989) The putative 5-HT3 agonist phenyl-biguanide induces carrier-mediated release of [3H]dopamine. Eur J Pharmacol 167:309–310

    Article  PubMed  Google Scholar 

  • Sellers EM, Romach MK, Frecker RC, Higgins GA (1991) Efficacy of the 5-HT3 antagonist ondansetron in addictive disorders. The role of ondansetron, a novel 5-HT3 antagonist in the treatment of psychiatrist disorders. Satellite Symposium of 5th World Congress of Biological Psychiatry, Florence, Italy

  • Sellers EM, Higgins GA, Sobell MB (1992) 5-HT and alcohol abuse. TIPS 13:69–75

    PubMed  Google Scholar 

  • Silverstone PH, Johnson B, Cowen PJ (1992) Does ondansetron attenuate amphetamine-induced behaviour in human volunteers? Psychopharmacology 107:140–141

    Article  PubMed  Google Scholar 

  • Sorensen S, Humphreys TM, Palfreyman MG (1989) Effect of acute and chronic MDL 73,147EF, a 5-HT3 receptor antagonist, on A9 and A10 dopamine neurones. Eur J Pharmacol 163:115–118

    Google Scholar 

  • Sullivan JT, Jasinski DR, Preston KL, Testa MP, Bell JM (1991) Cocaine blocking effects of ondansetron. Conference Proceedings, Committee on Problems of Drug Dependence, Richmond, VA, USA

  • Sugita S, Shen K-Z, North RA (1992) 5-Hydroxytryptamine is a fast excitatory transmitter at 5-HT3 receptors in rat amygdala. Neuron 8:199–203

    Article  PubMed  Google Scholar 

  • Svingos AL, Strecker RE, McNeish CS, Hitzermann R (1991) On the mechanisms by which 5-HT3 receptor antagonists inhibit cocaine-induced hyperactivity. Soc Neurosci Abstr 348.16

  • Tyers MB (1990) 5-HT3 Receptors. In: The neuropharmacology of serotonin. Ann NY Acad Sci 600:194–205

    PubMed  Google Scholar 

  • Van der Hoek GA, Cooper SJ (1990) Antagonism of amphetamine-induced sniffing, but not hyperlocomotion, by the selective 5-HT3 antagonist, ondansetron. Br J Pharmacol 100:414P

  • Van der Hoek GA, Cooper SJ, Jones BJ, Tyers MB (1989) Evidence that serotonin at 5-HT3 receptors modulates amphetamine-induced reward. Serotonin from cell biology to pharmacology and therapeutics. Conference Proceedings, Florence, Italy, p 55

  • Waeber C, Hoyer D, Palacios JM (1989) 5-Hydroxytryptamine receptors in the human brain, autoradiographic visualization using [3H]ICS 205–930. Neuroscience 31:393–400

    Article  PubMed  Google Scholar 

  • Wallis DI, Nash HL (1980) The action of methylated derivatives of 5-hydroxytryptamine at ganglionic receptors. Neuropharmacology 19:465–472

    Article  PubMed  Google Scholar 

  • Warburton EC, Feldon J, Weiner I, Gray JA, Joseph MH (1992) Antagonism of low dose amphetamine disruption of latent inhibition in rats by haloperidol and by the 5-HT3 antagonist ondansetron. J Psychopharmacol 6:110

    Google Scholar 

  • White A, Corn TH, Feetham C, Faulconbridge C (1991) Ondansetron in the treatment of schizophrenia. Lancet 337:1173

    Article  Google Scholar 

  • Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rec 4:469–492

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hagan, R.M., Kilpatrick, G.J. & Tyers, M.B. Interactions between 5-HT3 receptors and cerebral dopamine function: implications for the treatment of schizophrenia and psychoactive substance abuse. Psychopharmacology 112 (Suppl 1), S68–S75 (1993). https://doi.org/10.1007/BF02245009

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02245009

Key words

Navigation