The pharmacological properties of the presynaptic serotonin autoreceptor in the pig brain cortex conform to the 5-HT1D receptor subtype

  • E. Schlicker
  • K. Fink
  • M. Göthert
  • D. Hoyer
  • G. Molderings
  • I. Roschke
  • P. Schoeffter
Article
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Summary

The effects of serotonin receptor agonists and antagonists on the electrically (3 Hz) evoked 3H overflow were determined on pig brain cortex slices preincubated with 3H-serotonin and superfused with physiological salt solution containing indalpine (an inhibitor of serotonin uptake) plus phentolamine. The potencies of the serotonin receptor agonists and antagonists were compared with their affinities for 5-HT1A, 5-HT1B, 5-HT1c, and 5-HT1D binding sites in pig or rat tissue membranes; in addition, the potencies of the agonists were compared to their potencies in inhibiting adenylate cyclase activity in membranes of calf substantia nigra. In the superfusion experiments on pig brain cortex slices the following rank orders of potencies were obtained: agonists, serotonin > 5-methoxytryptamine = 5-carboxamidotryptamine >R U 24969 (5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole) > SDZ 21009 (4(3-terbutylamino- 2-hydroxypropoxy)indol- 2-carbonic-acid-isopropylester) ≥ yohimbine ≥ cyanopindolol > 8-OHDPAT (8-hydroxy-2-(di-n-propylamino)tetralin) ≥ CGS 12066 B (7-trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrrolo[1,2-a]quinoxaline); ipsapirone and urapidil were ineffective; antagonists (antagonism determined against 5methoxytryptamine as an agonist), metitepine > metergoline > mianserin. Propranolol, spiperone or mesulergine did not produce a shift of the concentration-response curve for 5-methoxytryptamine. The potencies of the serotonin receptor agonists in pig brain cortex slices were significantly correlated with their affinities for 5-HT1c and 5-HT1D binding sites in membranes of the pig choroid plexus and caudate nucleus, respectively, but not with their affinities for 5-HT1A and 5-HT1B sites in membranes of the cerebral cortex of pig and rat, respectively. The agonist potencies in decreasing 3H overflow were also significantly correlated with their potencies in inhibiting adenylate cylase activity in calf substantia nigra (i.e., a 5-HT1D receptor-mediated effect). In conclusion, the pig brain cortical 5-HT autoreceptor probably belongs to the 5-HT1D subtype. The involvement of 5-HT1c recognition sites was excluded by the low potency of mianserin as an antagonist and, in particular, by the ineffectiveness of the 5-HT1c receptor antagonist mesulergine.

Key words

Presynaptic 5-HT autoreceptors Serotonin release Pig brain cortex 5-HT binding sites 5-HT1D receptor 
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References

  1. Bonanno G, Maura G, Raiteri M (1986) Pharmacological characterization of release-regulating serotonin autoreceptors in rat cerebellum. Eur J Pharmcol 126:317–321Google Scholar
  2. Crist J, Surprenant A (1987) Evidence that 8-hydroxy-2-(n-dipropylamino) tetralin (8-OH-DPAT) is a selective α2-adrenoceptor antagonist on guinea-pig submucous neurones. Brit J Pharmacol 92:341–347Google Scholar
  3. Engel G, Göthert M, Müller-Schweinitzer E, Schlicker E, Sistonen L, Stadler PA (1983) Evidence for common pharmacological properties of [3H]5-hydroxytryptamine binding sites, presynaptic 5-hydroxytryptamine autoreceptors in CNS and inhibitory presynaptic 5-hydroxytryptamine receptors on sympathetic nerves. Naunyn-Schmiedeberg's Arch Pharmacol 324:116–124Google Scholar
  4. Engel G, Göthert M, Hoyer D, Schlicker E, Hillenbrand K (1986) Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites. Naunyn-Schmiedeberg's Arch Pharmacol 332:1–7Google Scholar
  5. Feuerstein TJ, Lupp A, Hertting G (1987) The serotonin (5-HT) autoreceptor in the hippocampus of the rabbit: role of 5-HT biophase concentration.Neuropharmacology 26:1071–1080Google Scholar
  6. Fink K, Schlicker E, Betz R, Göthert M (1988) Identification of presynaptic 5-HT1 autoreceptors in pig brain cortex synaptosomes and slices. Naunyn-Schmiedeberg's Arch Pharmacol 338:14–18Google Scholar
  7. Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blaschko H, Muscholl E (eds) Handbook of exper imental pharmacology, vol XXXIII. Springer, Berlin Heidelberg New York, pp 283–335Google Scholar
  8. Galzin AM, Chodkiewicz JP, Poirier MF, Loo H, Roux FX, Redondo A, Lista A, Ramdine R, Blier P, Langer SZ (1988) Modulation of the electrically-evoked release of [3H]-5-HT from slices of human frontal cortex. Brit J Pharmacol 93:14 PGoogle Scholar
  9. Göthert M (1982) Modulation of serotonin release in the brain via presynaptic receptors. Trends Pharmacol Sci 3:437–440Google Scholar
  10. Göthert M (1985) Role of autoreceptors in the function of the peripheral and central nervous system. Arzneimittelforschung 35:1909–1916Google Scholar
  11. Göthert M (1986) Serotonin receptors in the circulatory system. In: van Zwieten PA, Schönbaum E (eds) Progress in pharmacology, vol 6/2. Fischer, Stuttgart New York, pp 155–172Google Scholar
  12. Göthert M (1987) Inhibitory actions of serotonin (5-HT) on peripheral and central neurones. In: Rand MJ, Raper C (eds) Pharmacology, Excerpta Medica, International Congress Series No. 750. Elsevier, Amsterdam, pp 289–293Google Scholar
  13. Göthert M, Huth H, Schlicker E (1981) Characterization of the receptor subtype involved in alpha-adrenoceptor-mediated modulation of serotonin release from rat brain cortex slices. Naunyn-Schmiedeberg's Arch Pharmacol 317:199–203Google Scholar
  14. Hoyer D (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Recept Res 8:59–81Google Scholar
  15. Jackisch R, Kasakov L, Feuerstein TJ, Hertting G (1987) Effects of urapidil on neurotransmitter release in CNS tissue in vitro. Arch Int Pharmacodyn 285:5–24Google Scholar
  16. Limberger N, Bonanno G, Späth L, Starke K (1986) Autoreceptors and α2-adrenoceptors at the serotonergic axons of rabbit brain cortex. Naunyn-Schmiedeberg's Arch Pharmacol 332:324–331Google Scholar
  17. Maura G, Roccatagliata E, Raiteri M (1986) Serotonin autoreceptor in rat hippocampus: Pharmacological characterization as a subtype of the 5-HT1 receptor. Naunyn-Schmiedeberg's Arch Pharmacol 334:323–326Google Scholar
  18. Middlemiss DN, Bremer ME, Smith SM (1988) A pharmacological analysis of the 5-HT receptor mediating inhibition of 5-HT release in the guinea-pig frontal cortex. Eur J Pharmacol 157:101–107Google Scholar
  19. Moret C (1985) Pharmacology of the serotonin autoreceptor. In: Green AR (ed) Neuropharmacology of serotonin. Oxford University Press, Oxford New York Toronto Melbourne, pp 21–49Google Scholar
  20. Neale RF, Fallon SL, Boyar WC, Wasley JWF, Martin LL, Stone GA, Glaeser BS, Sinton CM, Williams M (1987) Biochemical and pharmacological characterization of CGS 12066 B, a selective serotonin-1B agonist. Eur J Pharmacol 136:1–9Google Scholar
  21. Peroutka SJ (1988) 5-Hydroxytryptamine receptor subtypes. Annu Rev Neurosci 11:45–60Google Scholar
  22. Rimele TJ, Henry DE, Lee DKH, Geiger G, Heaslip RJ, Grimes D (1987) Tissue-dependent alpha adrenoceptor activity of buspirone and related compounds. J Pharmacol Exp Ther 241:771–778Google Scholar
  23. Sachs L (1983) Angewandte Statistik. Anwendung statistischer Methoden. Springer, Berlin Heidelberg New York TokyoGoogle Scholar
  24. Schipper J, van der Heyden JAM, Olivier B (1987) Species differences in serotonin autoreceptors. Soc Neurosci Abstr vol 13, I, 345Google Scholar
  25. Schlicker E, Brandt F, Classen K, Göthert M (1985a) Serotonin release in human cerebral cortex and its modulation via serotonin receptors. Brain Res 331:337–341Google Scholar
  26. Schlicker E, Göthert M, Hillenbrand K (1985b) Cyanopindolol is a highly potent and selective antagonist at the presynaptic serotonin autoreceptor in the rat brain cortex. NaunynSchmiedeberg's Arch Pharmacol 331:398–401Google Scholar
  27. Schlicker E, Fink K, Betz R, Göthert M (1988a) The serotonin autoreceptor in the pig brain cortex belongs to the 5-HT1D receptor subtype. Naunyn-Schmiedeberg's Arch Pharmacol 338 (Suppl.):R67Google Scholar
  28. Schlicker E, Molderings G, Betz R, Göthert M (1988 b) Antagonistic properties of RU 24969, a preferential 5-HT1 receptor agonist, at presynaptic α2-adrenoceptors of central and peripheral neurones. Pharmacol Toxicol 63:281–285Google Scholar
  29. Schoeffter P, Waeber C, Palacios JM, Hoyer D (1988) The 5hydroxytryptamine 5-HT1D receptor subtype is negatively coupled to adenylate cyclase in calf substantia nigra. NaunynSchmiedeberg's Arch Pharmacol 337:602–608Google Scholar
  30. Starke K (1981) α-Adrenoceptor subclassification. Rev Physiol Biochem Pharmacol 88:199–236Google Scholar
  31. Starke K, Montel H, Gayk W, Merker R (1974) Comparison of the effects of clonidine on pre- and postsynaptic adrenoceptors in the rabbit pulmonary artery. α-Sympathomimetic inhibition of neurogenic vasoconstriction. Naunyn-Schmiedeberg's Arch Pharmacol 285:133–150Google Scholar
  32. Starke K, Göthert M, Kilbinger H (1989) Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev, in pressGoogle Scholar
  33. Timmermans PBMWM, Thoolen MJMC (1987) Autoreceptors in the central nervous system. Med Res Rev 7:307–332Google Scholar
  34. Waeber C, Schoeffter P, Palacios JM, Hoyer D (1988) Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes. NaunynSchmiedeberg's Arch Pharmacol 337:595–601Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • E. Schlicker
    • 1
  • K. Fink
    • 1
  • M. Göthert
    • 1
  • D. Hoyer
    • 2
  • G. Molderings
    • 1
  • I. Roschke
    • 1
  • P. Schoeffter
    • 2
  1. 1.Institut für Pharmakologie und Toxikologie der Rheinischen Friedrich-Wilhelms-Universität BonnBonnFederal Republic of Germany
  2. 2.Preclinical ResearchBaselSwitzerland

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