Skip to main content
SpringerLink
Log in

Influence of 5-HT3 Receptor Antagonists on Limbic-Cortical Circuitry

  • Chapter
Serotonin: Molecular Biology, Receptors and Functional Effects

  • 158 Accesses

Summary

Evidence is presented that 5-HT3 receptor antagonists such as ondansetron are highly effective in influencing behavioural disturbance in the absence of effect on normal behaviour. The 5-HT3 receptor antagonists demonstrate a remarkable potency and breadth of action over a wide dose range in rodent and primates to inhibit aversive behaviour, antagonise the hyperactivity caused by mesolimbic dopamine excess and facilitate performance in cognitive tests. These effects are achieved in the absence of withdrawal phenomana following cessation of chronic treatment. The studies indicate a widespread role for 5-HT3 receptors in the regulation of mesolimbic-cortical functioning, and the importance of the 5-HT3 receptor antagonists as investigative tools to establish the role of 5-HT3 receptors in anxiety, schizophrenia and cognitive dysfunction, and their treatment.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Ashby, C. R., Edwards, F., Harkins, K., and Wang, R. Y. (1989). Characterisation of 5-hydroxytryptamine3 receptors in the medial prefrontal cortex: a microiontopholetic study. Eur. J. Pharmacol. 173: 193–196.

    Article  Google Scholar 

  • Barnes, J. M., Barnes, N. M., Costall, B., Naylor, R. J., and Tyers, M. B. (1989). 5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue. Nature 338: 762–763.

    Google Scholar 

  • Barnes, J. M., Costall, B., Coughlan, J., Domeney, A. M., Gerrard, P. A., Kelly, M. E., Naylor, R. J., Onaivi, E. S., Tomkins, D. M., and Tyers, M. B. (1990). The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates. Pharmacol. Biochem. Behay. 35: 955–962.

    Article  Google Scholar 

  • Barnes, N. M., Costall, B., Ironside, J. W., and Naylor, R. J. (19886). Identification of 5-HT3 recognition sites in human brain using 3H.zacopride. J. Pharmac. Pharmacol. 40: 668.

    Article  Google Scholar 

  • Barnes, N. M., Costal!, B., and Naylor, R. J. (1988a). 3H.zacopride: a ligand for the identification of 5-HT3 recognition sites. J. Pharm. Pharmacol. 40: 548–551.

    Google Scholar 

  • Bartus, R. T., Dean, R. L., Beer, B., and Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417.

    Article  Google Scholar 

  • Bradley, P. B., Engel, G., Feniuk, G., Fozard, J. R., Humphrey, P. P. A., Middlemiss, D. N., Mylecharane, E. J., Richardson, B. P., and Saxena, P. R. (1986). Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacol. 25: 563–576.

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  • Costall, B., Domeney, A. M., Jones, B. N. C., and Naylor, R. J. (1988a). Assessment of behavioural parameters associated with anxiogenesis in the common marmoset (Callithrix jacchus). Br. J. Pharmacol. 95: 670P.

    Google Scholar 

  • Costall, B., Domeney, A. M., Naylor, R. J., and Tyers, M. B. (1987). Effects on the 5-HT3 receptor antagonist GR 38032F on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br. J. Pharmacol. 92: 881–894.

    Google Scholar 

  • Costall, B., Jones, B. J., Kelly, M. E., Naylor, R. J., Oakley, N. R., Onaivi, E. S., and Tyers, M. B. (1989). The effects of ondanestron (GR 38032F) in rats and mice treated subchronically with diazepam. Pharmacol. Biochem. Behay. 34: 769–778.

    Article  Google Scholar 

  • Costall, B., Jones, B. J., Kelly, M. E., Naylor, R. J., Onaivi, E. S., and Tyers, M. B. (1990a). Sites of action of ondansetron to inhibit withdrawal from drugs of abuse. Pharmacol. Biochem. Behay. 36: 97–104.

    Article  Google Scholar 

  • Costall, B., Kelly, M. E., Naylor, R. J., Onaivi, E. S., and Tyers, M. B. (1988b). Neuroanatomical sites of action of 5-HT3 receptor antagonists to alter exploratory behaviour of the mouse. Br. J. Pharmacol. 96: 325–332.

    Google Scholar 

  • Costall, B., and Naylor, R. J. (1990). 5-Hydroxytryptamine: new receptors and novel drugs for gastrointestinal motor disorders. Scand. J. Gastroenterol. 25: 769–787.

    Article  Google Scholar 

  • Costall, B., Naylor, R. J., and Tyers, M. B. (1990b). The psychopharmacology of 5-HT3 receptors. Pharmac. Ther. 47: 181–202.

    Article  Google Scholar 

  • Cutler, M. G., and Dixon, A. K. (1989). Effects of the 5-HT3 antagonist, ICS 205–930, on behaviour of mice during social encounters. Br. J. Pharmacol. 96: 12P.

    Google Scholar 

  • Cutler, M. G., and Dixon, A. K. (1989). Effects of the 5-HT3 antagonist, ICS 205–930, on behaviour of mice during social encounters. Br. J. Pharmacol. 96: 12P.

    Google Scholar 

  • Essman, W. B. (1978). Serotonin in learning and memory. In: Essman, W. B. (ed.) Serotonin in health and disease. Vol. III. The central nervous system. New York, Spectrum Publications, pp. 69–143.

    Google Scholar 

  • File, S. E. (1980). The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J. Neurosci. Meth. 2: 219–238.

    Article  Google Scholar 

  • File, S. E., and Johnston, A. L. (1989). Lack of effects of 5-HT3 receptor antagonists in the social interaction and elevated plus-maze tests of anxiety in the rat. Psychopharmacology 99: 248–251.

    Article  Google Scholar 

  • Fozard, J. R. (1984). MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn-Schmiedeberg’s Arch. Pharmacol. 326: 3644.

    Article  Google Scholar 

  • Grupp, L. A., Perlanski, E., and Stewart, R. B. (1988). Attenuation of alcohol intake by a serotonin uptake inhibitor: Evidence for mediation through the renin-angiotensin system. Pharmacol. Biochem. Behay. 30: 823–827.

    Article  Google Scholar 

  • Hagan, R. M., Butler, A., Hill, J. M., Jordan, C. C., Ireland, S. J., and Tyers, M. B. (1987). Effect of the 5-HT3 receptor antagonist, GR 38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of the rat brain. Eur. J. Pharmacol. 138: 303–305.

    Article  Google Scholar 

  • Hagan, R. M., Jones, B. J., Jordan, C. C., and Tyers, M. B. (1990). Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat. Br. J. Pharmacol. 99: 227–232.

    Google Scholar 

  • Higgins, G. A., Jones, B. J., Oakley, N. R., and Tyers, M. B. (1989). Evidence that the amygdala and not area postrema is involved in the putative anxiolytic effects of 5-HT3 receptor antagonists. Br. J. Pharmacol. 98: 635P.

    Google Scholar 

  • Ireland, S. J., and Tyers, M. B. (1987). Pharmacological characterisation of 5-hydroxytryptamine-induced depolarisation of the rat isolated vagus nerve. Br. J. Pharmacol. 90: 229–238.

    Google Scholar 

  • Johnston, A. L., and File, S. E. (1988). Effects of 5-HT3 antagonists in two animal tests of anxiety. Neurosci. Lett. 32: S44.

    Google Scholar 

  • Jones, B. J., Costall, B., Domeney, A. M., Kelly, M. E., Naylor, R. J., Oakley, N. R., and Tyers, M. B. (1988). The potential anxiolytic activity of GR 38032F, a 5-HT3 receptor antagonist. Br. J. Pharmacol. 93: 985–993.

    Google Scholar 

  • Kilfoil, T., Michael, A., Montgomery, D., and Whiting, R. L. (1989). Effects of anxiolytic and anxiogenic drugs on exploratory activity in a simple model of anxiety in mice. Neuropharmacology 28: 901–905.

    Article  Google Scholar 

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

    Article  Google Scholar 

  • Morinan, A. (1989). Effects of the 5-HT3 receptor antagonists, GR 38032F and BRL 24924 on anxiety in socially isolated rats. Br. J. Pharmacol. 97: 457P.

    Google Scholar 

  • Oakley, N. R., Jones, B. J., Tyers, M. B., Costall, B., and Domeney, A. M. (1988). The effect of ondansetron on alcohol consumption in the marmoset. Br. J. Pharmacol. 95: 870P.

    Google Scholar 

  • Onaivi, E. S., and Martin, B. R. (1989). Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white test box for the assessment of anxiety. Prog. Neuropsychopharmacol. Biol. Psychiat. 13: 963–976.

    Article  Google Scholar 

  • Papp, M., and Przegalinski, E. (1989). The 5-HT3 receptor antagonists ICS 205–930 and GR 38032F, putative anxiolytic drugs, differ from diazepam in their pharmacological profile. J. Psychopharmacol. 3: 14–20.

    Article  Google Scholar 

  • Piper, D., Upton, N., Thomas, D., and Nicholson, J. (1988). The effects of the 5-HT3 receptor antagonists BRL 43694 and GR 38032F in animal behavioural models of anxiety. Br. J. Pharmacol. 94: 314P.

    Google Scholar 

  • Richardson, B. P., Engel, S., Donatsch, P., and Stadler, P. A. (1985). Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 316: 125–131.

    Google Scholar 

  • Sellers, E. M., Kaplan, H. L., Lawrin, M. O., Somer, G., Noranjo, C. A., and Frecker, R. C. (1988). The 5-HT3 antagonist GR 38032F decreases alcohol consumption in rats. Soc. Neurosci. 18th An. Meet. Toronto Abstr. 21. 4.

    Google Scholar 

  • Sorensen, S. M., Humphreys, T. M., and Palfreyman, M. G. (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.

    Article  Google Scholar 

  • Vogel, J. R., Beer, B., and Clody, D. E. (1971). A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacology 21: 1–7.

    Article  Google Scholar 

  • Young, R., and Johnson, D. N. (1988). Comparative effects of zacopride, GR 38032F, buspirone and diazepam in the mouse light/dark exploratory model. Soc. Neurosci. Abst. 14: 207.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Postgraduate Studies in Pharmacology, The School of Pharmacy, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK

    B. Costall & R. J. Naylor

Authors
  1. B. Costall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. J. Naylor
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Preclinical Research, Sandoz Pharma Ltd., P.O. Box 6, CH-4002, Basel, Switzerland

    John R. Fozard

  2. Institute of Pharmacology, Erasmus University Rotterdam, P.O. Box 1738, NL-3000 DR, Rotterdam, The Netherlands

    Pramod R. Saxena

Rights and permissions

Reprints and permissions

Copyright information

© 1991 Birkhäuser Verlag Basel/Switzerland

About this chapter

Cite this chapter

Costall, B., Naylor, R.J. (1991). Influence of 5-HT3 Receptor Antagonists on Limbic-Cortical Circuitry. In: Fozard, J.R., Saxena, P.R. (eds) Serotonin: Molecular Biology, Receptors and Functional Effects. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7259-1_43

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-7259-1_43

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-0348-7261-4

  • Online ISBN: 978-3-0348-7259-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation