Skip to main content
SpringerLink
Log in

The Murine Serotonin Syndrome and the 5-HT1A Receptor: Behavioral Effects and Hypothermia

  • Protocol
  • First Online:
Serotonin Receptor Technologies

Part of the book series: Neuromethods ((NM,volume 95))

  • 796 Accesses

Abstract

The serotonin syndrome in humans is caused by severe side effects of drugs that either increase the extracellular serotonin (5-HT) concentration or are agonists at 5-HT receptors. The symptoms include mental state alterations (e.g., agitation, confusion), neuromuscular excitation (e.g., myoclonus, tremor), and autonomic dysregulation (e.g., hyperthermia, tachycardia). Similar symptoms can also be induced in rodents, especially in rats, whereas in mice the serotonin syndrome is not as clearly defined. Based on current literature and our own experimental studies in mice we will discuss in this chapter the validity of the murine model for the serotonin syndrome with special emphasis on the contribution of different 5-HT receptor subtypes focusing on the 5-HT1A receptor. We will provide a field manual to study changes in behavior and in body temperature. Behavioral changes characteristic for the serotonin syndrome should be assessed simultaneously after application of drugs consistently affecting the serotonergic system. A change in body temperature constitutes an important vegetative endpoint which can also be affected by drugs interfering with 5-HT metabolism and/or acting as 5-HT receptor agonists. The radiotelemetry technique allows to continuously monitor dose- and time-related drug effects without handling the animal. In general, the murine model for the serotonin syndrome is a valuable tool to study serotonin-induced hyperactivity for both basic and preclinical research in order to identify drugs or drug combinations with potential risk to induce a serotonin syndrome in man.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover 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

References

  1. Boyer EW, Shannon M (2005) The serotonin syndrome. N Engl J Med 352:1112–1120

    Article  CAS  PubMed  Google Scholar 

  2. Loizou LA (1970) Uptake of monoamines into central neurones and the blood-brain barrier in the infant rat. Br J Pharmacol 40:800–813

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Lopez-Munoz F, Alamo C (2009) Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm Des 15:1563–1586

    Article  CAS  PubMed  Google Scholar 

  4. Bogdanski DF, Weissbach H, Udenfriend S (1958) Pharmacological studies with the serotonin precursor, 5-hydroxytryptophan. J Pharmacol Exp Ther 122:182–194

    CAS  PubMed  Google Scholar 

  5. Page IH (1958) Serotonin (5-hydroxytryptamine); the last four years. Physiol Rev 38:277–335

    CAS  PubMed  Google Scholar 

  6. Jacobs BL (1974) Effect of two dopamine receptor blockers on a serotonin-mediated behavioral syndrome in rats. Eur J Pharmacol 27:363–366

    Article  CAS  PubMed  Google Scholar 

  7. Hwang EC, Van Woert MH (1979) Behavioral and biochemical actions of p-chlorophenylethylamine (p-CPEA) in mice. Life Sci 24:595–601

    Article  CAS  PubMed  Google Scholar 

  8. Kalueff AV, LaPorte JL, Murphy DL (2008) Perspectives on genetic animal models of serotonin toxicity. Neurochem Int 52:649–658

    Article  CAS  PubMed  Google Scholar 

  9. Haberzettl R, Bert B, Fink H, Fox MA (2013) Animal models of the serotonin syndrome: a systematic review. Behav Brain Res 256:328–345

    Article  CAS  PubMed  Google Scholar 

  10. Bert B, Fink H, Hortnagl H, Veh RW, Davies B, Theuring F, Kusserow H (2006) Mice over-expressing the 5-HT(1A) receptor in cortex and dentate gyrus display exaggerated locomotor and hypothermic response to 8-OH-DPAT. Behav Brain Res 167:328–341

    Article  CAS  PubMed  Google Scholar 

  11. Blanchard RJ, Griebel G, Guardiola-Lemaitre B, Brush MM, Lee J, Blanchard DC (1997) An ethopharmacological analysis of selective activation of 5-HT1A receptors: the mouse 5-HT1A syndrome. Pharmacol Biochem Behav 57:897–908

    Article  CAS  PubMed  Google Scholar 

  12. Diaz SL, Maroteaux L (2011) Implication of 5-HT(2B) receptors in the serotonin syndrome. Neuropharmacology 61:495–502

    Article  CAS  PubMed  Google Scholar 

  13. Fox MA, Jensen CL, Gallagher PS, Murphy DL (2007) Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice. Neuropharmacology 53:643–656

    Article  CAS  PubMed  Google Scholar 

  14. Yamada J, Sugimoto Y, Horisaka K (1988) The behavioural effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in mice. Eur J Pharmacol 154:299–304

    Article  CAS  PubMed  Google Scholar 

  15. Verge D, Daval G, Marcinkiewicz M, Patey A, el Mestikawy S, Gozlan H, Hamon M (1986) Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 6:3474–3482

    CAS  PubMed  Google Scholar 

  16. Blier P, Lista A, De Montigny C (1993) Differential properties of pre- and postsynaptic 5-hydroxytryptamine1A receptors in the dorsal raphe and hippocampus: I. Effect of spiperone. J Pharmacol Exp Ther 265:7–15

    CAS  PubMed  Google Scholar 

  17. Smith LM, Peroutka SJ (1986) Differential effects of 5-hydroxytryptamine1a selective drugs on the 5-HT behavioral syndrome. Pharmacol Biochem Behav 24:1513–1519

    Article  CAS  PubMed  Google Scholar 

  18. Bill DJ, Knight M, Forster EA, Fletcher A (1991) Direct evidence for an important species difference in the mechanism of 8-OH-DPAT-induced hypothermia. Br J Pharmacol 103:1857–1864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Hedlund PB, Kelly L, Mazur C, Lovenberg T, Sutcliffe JG, Bonaventure P (2004) 8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents. Eur J Pharmacol 487:125–132

    Article  CAS  PubMed  Google Scholar 

  20. Fox MA, French HT, LaPorte JL, Blackler AR, Murphy DL (2010) The serotonin 5-HT(2A) receptor agonist TCB-2: a behavioral and neurophysiological analysis. Psychopharmacology (Berl) 212:13–23

    Article  CAS  Google Scholar 

  21. Kalueff AV, Fox MA, Gallagher PS, Murphy DL (2007) Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice. Genes Brain Behav 6:389–400

    Article  CAS  PubMed  Google Scholar 

  22. Fox MA, Panessiti MG, Moya PR, Tolliver TJ, Chen K, Shih JC, Murphy DL (2013) Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans. Pharmacogenomics J 13:551–557

    Article  CAS  PubMed  Google Scholar 

  23. Fox MA, Jensen CL, French HT, Stein AR, Huang SJ, Tolliver TJ, Murphy DL (2008) Neurochemical, behavioral, and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice. Psychopharmacology (Berl) 201:203–218

    Article  CAS  Google Scholar 

  24. Ma Z, Zhang G, Jenney C, Krishnamoorthy S, Tao R (2008) Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats. Eur J Pharmacol 588:198–206

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Zhang G, Krishnamoorthy S, Ma Z, Vukovich NP, Huang X, Tao R (2009) Assessment of 5-hydroxytryptamine efflux in rat brain during a mild, moderate and severe serotonin-toxicity syndrome. Eur J Pharmacol 615:66–75

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM (2003) The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J Med 96:635–642

    Article  CAS  Google Scholar 

  27. Sternbach H (1991) The serotonin syndrome. Am J Psychiatry 148:705–713

    CAS  PubMed  Google Scholar 

  28. Adriaan Bouwknecht J, Olivier B, Paylor RE (2007) The stress-induced hyperthermia paradigm as a physiological animal model for anxiety: a review of pharmacological and genetic studies in the mouse. Neurosci Biobehav Rev 31:41–59

    Article  CAS  PubMed  Google Scholar 

  29. van Bogaert MJ, Groenink L, Oosting RS, Westphal KG, van der Gugten J, Olivier B (2006) Mouse strain differences in autonomic responses to stress. Genes Brain Behav 5:139–149

    Article  PubMed  Google Scholar 

  30. Clement JG, Mills P, Brockway B (1989) Use of telemetry to record body temperature and activity in mice. J Pharmacol Methods 21:129–140

    Article  CAS  PubMed  Google Scholar 

  31. Zuther P, Gorbey S, Lemmer B (2009) Chronos-Fit 1.06. http://www.ma.uni-heidelberg.de/inst/phar/lehre/chrono.html

  32. Goecke JC, Awad H, Lawson JC, Boivin GP (2005) Evaluating postoperative analgesics in mice using telemetry. Comp Med 55:37–44

    CAS  PubMed  Google Scholar 

  33. Hayes KE, Raucci JA Jr, Gades NM, Toth LA (2000) An evaluation of analgesic regimens for abdominal surgery in mice. Contemp Top Lab Anim Sci 39:18–23

    CAS  PubMed  Google Scholar 

  34. Perry KW, Fuller RW (1989) Determination of brain concentrations of 8-hydroxy-2-(di-n-propylamino)tetralin by liquid chromatography with electrochemical detection. Biochem Pharmacol 38:3169–3173

    Article  CAS  PubMed  Google Scholar 

  35. Hirano K, Kimura R, Sugimoto Y, Yamada J, Uchida S, Kato Y, Hashimoto H, Yamada S (2005) Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors. Br J Pharmacol 144:695–702

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Saadat KS, O’Shea E, Colado MI, Elliott JM, Green AR (2005) The role of 5-HT in the impairment of thermoregulation observed in rats administered MDMA (‘ecstasy’) when housed at high ambient temperature. Psychopharmacology (Berl) 179:884–890

    Article  CAS  Google Scholar 

  37. Ogren SO, Carlsson S, Bartfai T (1985) Serotonergic potentiation of muscarinic agonist evoked tremor and salivation in rat and mouse. Psychopharmacology (Berl) 86:258–264

    Article  CAS  Google Scholar 

  38. Haberzettl R, Fink H, Bert B (2014) The murine serotonin syndrome - Evaluation of responses to 5-HT-enhancing drugs in NMRI mice. Behav Brain Res doi: 10.1016/j.bbr.2014.04.033.

  39. Haberzettl R, Fink H, Bert B (2014) Role of 5-HT1A- and 5-HT2A receptors for the murine model of the serotonin syndrome. J Pharmacol Toxicol Methods 70(2):129–33

    Google Scholar 

Download references

Acknowledgments

Robert Haberzettl received financial support from the Elsa-Neumann-Doctoral-Fellowship from the state Berlin, Germany.

Author information

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, Koserstrasse 20, 14195, Berlin, Germany

    Robert Haberzettl, Heidrun Fink, Silke Dietze & Bettina Bert

Authors
  1. Robert Haberzettl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heidrun Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silke Dietze
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bettina Bert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bettina Bert .

Editor information

Editors and Affiliations

  1. Universität zu Köln, Köln, Germany

    Wolfgang Blenau

  2. Forschungszentrum Jülich, Jülich, Germany

    Arnd Baumann

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this protocol

Cite this protocol

Haberzettl, R., Fink, H., Dietze, S., Bert, B. (2015). The Murine Serotonin Syndrome and the 5-HT1A Receptor: Behavioral Effects and Hypothermia. In: Blenau, W., Baumann, A. (eds) Serotonin Receptor Technologies. Neuromethods, vol 95. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2187-4_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-2187-4_5

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-2186-7

  • Online ISBN: 978-1-4939-2187-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation