Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 345, Issue 2, pp 129–136 | Cite as

Evidence for various tryptamines and related compounds acting as substrates of the platelet 5-hydroxytryptamine transporter

  • Reinhard Wölfel
  • Karl-Heinz Graefe


The aim of the present study was to answer the question whether amines other than 5-hydroxytryptamine (5-HT) and tryptamine act as substrates of the platelet 5-HT transporter. To this end, a large number of tryptamines, 5-HT receptor agonists and phenethylamines (which had IC50 values for 3H-5-HT uptake inhibition of 145–24500 nmol l−1) was examined in rabbit platelets in order to determine their ability to induce an outward transport of 3H-5-HT Platelets (the MAO of which was blocked) from reserpine-pretreated animals were loaded with 3H-5-HT and then exposed for 5 min to various concentrations (ranging from 0.25 to 40 times the IC50) of each compound. The concentration-effect curves for the drug-induced increase in 3H-5-HT efflux served to determine values of Emax (maximum increase in efflux expressed in % of the 3H-5-HT content of cells) and EC50 (drug concentration producing Emax/2).

For the 24 compounds studied here (which included the 5-HT uptake inhibitors imipramine, citalopram, fluoxetine and cocaine) a linear correlation between EC50 and IC50 (r = 0.975) and a mean ratio of EC50/IC50 of 2.4 was found. Most of the compounds [e.g., (±)8-hy-ydroxy-2-(N,N-dipropylamino)tetralin, S(+)α-methyl-5-HT, 5-carboxamidotryptamine and 5-methoxytryptamine] gave rise to Emax values (15.8–32.5%) that exceeded that brought about by imipramine (6.6%), indicating that they act as substrates of the 5-HT transporter; the 3H-5-HT outward transport observed in response to these substances was abolished in the presence of imipramine. Others (e.g., 2-methyl-5-HT and 5-methylurapidil) produced Emax values (3.4–14.3%) not significantly different from that of imipramine and, therefore, can be classified either as poor substrates or as inhibitors of the 5-HT transporter.

Hence, many tryptamines and 5-HT receptor agonists are substrates of the platelet 5-HT transporter. The property of being substrates gives them the latent capacity to bring about release of endogenous 5-HT and, as a result, to cause indirect 5-HT receptor-mediated effects.

Key words

Rabbit platelets 5-HT transporter Carrier-mediated efflux Tryptamines 5-HT receptor agonists 



monoamine oxidase






























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  1. Bönisch H, Trendelenburg U (1988) Mechanism of action of indirectly acting sympathomimetic amines. In: Trendelenburg U, Weiner N (eds) Handbook of Experimental Pharmacology, vol 90. Catecholamines I. Springer, Berlin Heidelberg New York London Paris Tokyo, pp 246–277Google Scholar
  2. Born GVR, Juengjaroen K, Michal F (1972) Relative activities on and uptake by human blood platelets of 5-hydroxytryptamine and several analogues. Br J Pharmacol 44:117–139Google Scholar
  3. Bradley PB, Engel G, Feniuk W, Fozard JR, Humphrey PPA, Middlemiss DN, Mylecharane EJ, Richardson BP, Saxena PR (1986) Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology 25:563–576Google Scholar
  4. Fuller RW, Perry KW, Molloy BB (1975) Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine. Eur J Pharmacol 33:119–124Google Scholar
  5. Garattini S, Caccia S, Mennini T, Samanin R, Consolo S, Ladinsky H (1979) Biochemical pharmacology of the anorectic drug fenfluramine: a review. Curr Med Res Opinion 6 [Suppl 1]:15–27Google Scholar
  6. Given MB, Longenecker GL (1985) Characteristics of serotonin uptake and release by platelets. In: Longenecker GL (ed) The platelets, physiology and pharmacology. Academic Press, Orlando San Diego New York London Toronto Montreal Sydney Tokyo, pp 463–479Google Scholar
  7. Gordon JL, Olverman HJ (1978) 5-Hydroxytryptamine and dopamine transport by rat and human blood platelets. Br J Pharmacol 62:219 -226Google Scholar
  8. Groß G, Hanft G, Kolassa N (1987) Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for α1-adrenoceptor binding sites. Naunyn-Schmiedeberg's Arch Pharmacol 336:597–601Google Scholar
  9. Hjorth S, Carlsson A, Lindberg P, Sanchez D, Wilkstrom HH, Arvidsson LE, Hacksell V, Nilsson JLG (1981) 8-Hydroxy-2-(di-n-propylamino)tetralin; central 5-HT receptor stimulating activity. Psychopharmacol Bull 17:180–183Google Scholar
  10. Hyttel J (1977) Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu 10–171. Psychopharmacology 51:225–233Google Scholar
  11. Hyttel J (1982) Citalopram — pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Progr Neuro-Psychopharmacol Biol Psychiatry 6:277–295Google Scholar
  12. Martin LL, Sanders-Bush E (1982) Comparison of the pharmacology characteristics of 5-HT1 and 5-HT2 binding sites with those of serotonin autoreceptors which modulate serotonin release. NaunynSchmiedeberg's Arch Pharmacol 321:165–170Google Scholar
  13. Nelson PJ, Rudnick G (1979) Coupling between platelet 5-hydroxytryptamine and potassium transport. J Biol Chem 254:10084–10089Google Scholar
  14. Nelson PJ, Rudnick G (1982) The role of chloride ion in platelet serotonin transport. J Biol Chem 257:6151–6155Google Scholar
  15. Omenn GS, Smith LT (1978) A common uptake system for serotonin and dopamine in human platelets. J Clin Invest 62:235–240Google Scholar
  16. O'Reilly CA, Reith MEA (1988) Uptake of 3H-serotonin into plasma membrane vesicles from mouse cerebral cortex. J Biol Chem 263:6115–6121Google Scholar
  17. Paton DM (1976) Characteristics of efflux of noradrenaline from adrenergic neurons. In: Paton DM (ed) The mechanism of neuronal and extraneuronal transport of catecholamines. Raven Press, New York, pp 155–174Google Scholar
  18. Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of 3H-5-hydroxytryptamine, 3H-lysergic acid diethylamide and 3H-spiroperidol. Mol Pharmacol 16:687–699Google Scholar
  19. Ross SB, Ask A-L (1980) Structural requirements for uptake into serotoninergic neurones. Acta Pharmacol Toxicol 46:270–277Google Scholar
  20. Rudnick G, Talvenheimo J, Fishkes H, Nelson PJ (1983) Sodium ion requirements for serotonin transport and imipramine binding. Psychopharmacol Bull 19:545–549Google Scholar
  21. Segonzac A, Tateishi T, Langer SZ (1984) Saturable uptake of 3H-tryptamine in rabbit platelets is inhibited by 5-hydroxytryptamine uptake blockers. Naunyn-Schmiedeberg's Arch Pharmacol 328:33–37Google Scholar
  22. Segonzac A, Raisman R, Tateishi T, Shoemaker H, Hicks PE, Langer SZ (1985) Tryptamine, a substrate for the serotonin transporter in human platelets, modifies the dissociation kinetics of 3H-imipramine binding: possible allosteric interaction. J Neurochem 44:349–356Google Scholar
  23. Sneddon JM (1973) Blood platelets as a model for monoamine-containing neurones. Progr Neurobiol 1:151–108Google Scholar
  24. Stacey RS (1961) Uptake of 5-hydroxytryptamine by platelets. Br J Pharmacol 16:284–295Google Scholar
  25. Stahl SM (1985) Platelets as pharmacological models for the receptors and biochemistry of monoaminergic neurons. In: Longenecker GL (ed) The platelets, physiology and pharmacology. Academic Press, Orlando San Diego New York London Toronto Montreal Sydney Tokyo, pp 307–340Google Scholar
  26. Talvenheimo J, Nelson PJ, Rudnick G (1979) Mechanism of imipramine inhibition of platelet 5-hydroxytryptamine transport. J Biol Chem 254:4631–4635Google Scholar
  27. Talvenheimo J, Fishkes H, Nelson PJ, Rudnick G (1983) The serotonin transporter-imipramine “receptor”; different sodium requirements for imipramine binding and serotonin translocation. J Biol Chem 258:6115–6119Google Scholar
  28. Trendelenburg U (1978) Release induced by phenethylamines. In: Paton DM (ed) The release of catecholamines from adrenergic neurons. Pergamon Press, Oxford New York, pp 333–354Google Scholar
  29. Tricklebank MD, Forler C, Middlemiss DN, Fozard JR (1985) Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat. Eur J Pharmacol 117:15–24Google Scholar
  30. Wallenstein S, Zucker CL, Fleiss JL (1980) Some statistical methods useful in circulation research. Circ Res 47:1–9Google Scholar
  31. Wölfel R, Böhm W, Halbrügge T, Bönisch H, Graefe K-H (1988) On the 5-hydroxytryptamine transport across the plasma membrane of rabbit platelets and its inhibition by imipramine. Naunyn-Schmiedeberg's Arch Pharmacol 338:1–8Google Scholar
  32. Wölfel R, Graefe K-H (1991a) Evidence for 5-hydroxytryptamine (5-HT) receptor agonists acting as substrates of the 5-HT transporter in rabbit platelets. Naunyn-Schmiedeberg's Arch Pharmacol 343 [Suppl]:R100Google Scholar
  33. Wölfel R, Graefe K-H (1991b) Effects of imipramine and some tryptamine derivatives on the efflux of 3H-5-hydroxytryptamine from rabbit platelets. J Neur Transm Suppl 34:77–83Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Reinhard Wölfel
    • 1
  • Karl-Heinz Graefe
    • 1
  1. 1.Institut für Pharmakologie und Toxikologie der Universität WürzburgWürzburgFederal Republic of Germany

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