Advertisement

Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 343, Issue 4, pp 353–364 | Cite as

Species differences in presynaptic serotonin autoreceptors: mainly 5-HT1B but possibly in addition 5-HT1D in the rat, 5-HT1D in the rabbit and guinea-pig brain cortex

  • N. Limberger
  • R. Deicher
  • K. Starke
Article

Summary

The pharmacological properties of presynaptic serotonin autoreceptors were compared in slices of rat, rabbit, and guinea-pig brain cortex. The slices were preincubated with 3H-serotonin and then superfused with medium containing fluvoxamine 3 μmol/l and stimulated four times by trains of four pulses delivered at 100 Hz. Cumulative concentration-response curves were determined and used for the calculation of agonist EC50 values and maximal effects and antagonist KB values.

Unlabelled serotonin itself and the serotonin receptor agonists 5-carboxamidotryptamine (5-CT), 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) and (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reduced the stimulation-evoked overflow of tritium with a rank order of potency 5-CT = RU 24969 > serotonin > 8-OH-DPAT in the rat and 5-CT > serotonin > RU 24969 > 8-OH-DPAT in the rabbit and guinea-pig. Ipsapirone caused no change. Metitepine and metergoline antagonized the effect of 5-CT; the KB values were lower in the rabbit and guinea-pig than in the rat. Yohimbine at up to 1 μmol/1 did not reduce the evoked overflow of tritium and did not antagonize the inhibitory effect of 5-CT in the rat but reduced the evoked overflow in the rabbit and counteracted the effect of 5-CT in the guinea-pig. (−)-Propranolol, conversely, reduced the evoked overflow of tritium in the rat but neither reduced the evoked overflow nor antagonized the effect of 5-CT in the rabbit and guinea-pig. Isamoltane did not significantly change the effect of 5-CT in any species. In the rat, it also failed to antagonize the inhibitory effect of 8-OH-DPAT but did antagonize the effect of RU 24969. The inhibition caused by 8-OH-DPAT persisted in the presence of idazoxan but was attenuated by metitepine in all species.

The experimental conditions used permit the determination of the constants of agonist and antagonist action undistorted by autoinhibition. The results confirm the view that the serotonin axons of rat brain possess 5-HT1B autoreceptors. They show by direct comparison under identical conditions that the autoreceptors in rabbit and guinea-pig are very similar to each other but differ markedly from those in the rat. The results give additional credence to previous suggestions that, in the rabbit and guinea-pig, the autoreceptors are 5-HT1D. The serotonin axons of rat brain cortex may possess 5-1D in addition to 5-HT1B autoreceptors. In many previous studies agonist potencies at, and antagonist affinities for, presynaptic serotonin autoreceptors have been underestimated due to the use of too intense stimuli to elicit serotonin release.

Key words

Serotonin release Serotonin receptors Autoreceptors Species differences 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58Google Scholar
  2. Bonanno G, Maura G, Raiteri M (1986) Pharmacological characterization of release-regulating serotonin autoreceptors in rat cerebellum. Eur J Pharmacol 126:317–321CrossRefGoogle 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 25:563–576CrossRefGoogle Scholar
  4. 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. Br J Pharmacol 92:341–347CrossRefGoogle Scholar
  5. Dumuis A, Sebben M, Bockaert J (1989) The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn-Schmiedeberg's Arch Pharmacol 340:403–410CrossRefGoogle Scholar
  6. 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 324:116–124CrossRefGoogle Scholar
  7. 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 332:1–7CrossRefGoogle Scholar
  8. Feuerstein TJ, Hertting GJackisch R (1985) Endogenous noradrenaline as modulator of hippocampul serotonin (5-HT)-release. Naunyn-Schmiedeberg's Arch Pharmacol 329:216–221CrossRefGoogle Scholar
  9. 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 26:1071–1080CrossRefGoogle Scholar
  10. Fischer MRG, Limberger N, Starke K (1990) The transmitter release pattern of serotonin axons in rabbit brain cortex slices during short pulse trains. Neurochem Int 17:129–137CrossRefGoogle Scholar
  11. Galzin AM, Blier P, Chodkiewicz JP, Poirier MF, Loo H, Roux FX, Bedondo A, Lista A, Ramdine R, Langer SZ (1988) Pharmacological characterization of the serotonin (5-HT) autoreceptor modulating the electrically-evoked release of [3H]-5-HT from slices of human frontal cortex. Soc Neurosci Abstr 14:313Google Scholar
  12. Göthert M, Schlicker E (1983) Autoreceptor-mediated inhibition of 3H-5-hydroxytryptamine release from rat brain cortex slices by analogues of 5-hydroxytryptamine. Life Sci 32:1183–1191CrossRefGoogle 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 317:199–203CrossRefGoogle Scholar
  14. Göthert M, Schlicker E, Fink K, Classen K (1987) Effects of RU 24969 on serotonin release in rat brain cortex: further support for the identity of serotonin autoreceptors with 5-HT1B sites. Arch Int Pharmacodyn 288:31–42PubMedGoogle Scholar
  15. Hamon M, Bourgoin S, Gozlan H, Hall MD, Goetz C, Artaud F, Horn AS (1984) Biochemical evidence for the 5-HT agonist properties of PAT (8-hydroxy-2-(di-n-propylamino)tetratin) in the rat brain. Eur J Pharmacol 100:263–276CrossRefGoogle Scholar
  16. Herrick-Davis K, Titeler M (1988) Detection and characterization of the serotonin 5-HT1D receptor in rat and human brain. J Neurochem 50:1624–1631CrossRefGoogle Scholar
  17. Heuring RE, Peroutka SJ (1987) Characterization of a novel 3H-5-hydroxytryptamine binding site subtype in bovine brain membranes. J Neurosci 7:894–903CrossRefGoogle Scholar
  18. Hoyer D, Middlemiss DN (1989) Species differences in the pharmacology of terminal 5-HT autoreceptors in mammalian brain. Trends Pharmacol Sci 10:130–132CrossRefGoogle Scholar
  19. Leonhardt S, Herrick-Davis K, Titeler M (1989) Detection of a novel serotonin receptor subtype (5-HT1E) in human brain: interaction with a GTP-binding protein. J Neurochem 53:465–471CrossRefGoogle Scholar
  20. Limberger N, Bonanno G, Späth L, Starke K (1986) Autoreceptors and α2-adrenoceptors at the serotonin axons of rabbit brain cortex. Naunyn-Schmiedeberg's Arch Pharmacol 332:324–331CrossRefGoogle Scholar
  21. Limberger N, Mayer A, Zier G, Valenta B, Starke K, Singer EA (1989) Estimation of pA2 values at presynaptic α2-autoreceptors in rabbit and rat brain cortex in the absence of autoinhibition. Naunyn-Schmiedeberg's Arch Pharmacol 340:639–647CrossRefGoogle Scholar
  22. Limberger N, Starke K, Singer EA (1990) Serotonin uptake blockers influence serotonin autoreceptors by increasing the biophase concentration of serotonin and not through a “molecular link”. Naunyn-Schmiedeberg's Arch Pharmacol 342:363–370CrossRefGoogle Scholar
  23. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  24. Martin LL, Sanders-Bush E (1982) Comparison of the pharmacological characteristics of 5-HT1 and 5-HT2 binding sites with those of serotonin autoreceptors which modulate serotonin release. Naunyn-Schmiedeberg's Arch Pharmacol 321:165–170CrossRefGoogle Scholar
  25. 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 334:323–326CrossRefGoogle Scholar
  26. Maura G, Ulivi M, Raiteri M (1987) (−)-Propranolol and (±)-cyanopindolol are mixed agonists-antagonists at serotonin autoreceptors in the hippocampus of the rat brain. Neuropharmacology 26:713–717CrossRefGoogle Scholar
  27. Middlemiss DN (1984a) Stereoselective blockade at [3H]5-HT binding sites and at the 5-HT autoreceptor by propranolol. Eur J Pharmacol 101:289–293CrossRefGoogle Scholar
  28. Middlemiss DN (1984b) 8-Hydroxy-2-(di-n-propylamino) tetralin is devoid of activity at the 5-hydroxytryptamine autoreceptor in rat brain. Implications for the proposed link between the autoreceptor and the [3H]5-HT recognition site. Naunyn-Schmiedeberg's Arch Pharmacol 327:18–22CrossRefGoogle Scholar
  29. Middlemiss DN (1985) The putative 5-HT1 receptor agonist, RU 24969, inhibits the efflux of 5-hydroxytryptamine from rat frontal cortex slices by stimulation of the 5-HT autoreceptor. J Pharm Pharmacol 37:434–437CrossRefGoogle Scholar
  30. 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 157:101–107CrossRefGoogle Scholar
  31. Motulsky HJ, Ransnas LA (1987) Fitting curves to data using nonlinear regression: a practical and nonmathematical review. FASEB J 1:365–374CrossRefGoogle Scholar
  32. Richards MH (1985) Efflux of 3H-5-hydroxytryptamine from rat hypothalamic slices by continuous electrical stimulation: frequency-dependent responses to serotonergic antagonists and 5-hydroxytryptamine. Naunyn-Schmiedeberg's Arch Pharmacol 329:359–366CrossRefGoogle Scholar
  33. Schipper J (1990) Pharmacological characterization of serotonin autoreceptors. Pharmacol Toxicol 66, Suppl 111:149Google Scholar
  34. Schipper J, Tulp MTM (1988) Serotonin autoreceptors in guinea pig cortex slices resemble the 5-HT1D binding site. Soc Neurosci Abstr 14:552Google Scholar
  35. Schlicker E, Fink K, Göthert M, Hoyer D, Molderings G, Roschke I, Schoeffter P (1989) The pharmacological properties of the presynaptic serotonin autoreceptor in the pig brain cortex conform to the 5-HT1D receptor subtype. Naunyn-Schmiedeberg's Arch Pharmacol 340:45–51Google Scholar
  36. Schoeffter P, Hoyer D (1989a) Interaction of arylpiperazines with 5-HT1A 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist? Naunyn-Schmiedeberg's Arch Pharmacol 339:675–683CrossRefGoogle Scholar
  37. Schoeffter P, Hoyer D (1989b) 5-Hydroxytryptamine 5-HT1B and 5-HT1D receptors mediating inhibition of adenylate cyclase activity. Naunyn-Schmiedeberg's Arch Pharmacol 340:285–292Google Scholar
  38. Schoeffter P, Hoyer D (1990) 5-Hydroxytryptamine (5-HT)-induced endothelium-dependent relaxation of pig coronary arteries is mediated by 5-HT receptors similar to the 5-HT1D receptor subtype. J Pharmacol Exp Ther 252:387–395PubMedGoogle Scholar
  39. Shenker A, Maayani S, Weinstein H, Green JP (1987) Pharmacological characterization of two 5-hydroxytryptamine receptors coupled to adenylate cyclase in guinea pig hippocampal membranes. Mol Pharmacol 31:357–367PubMedGoogle Scholar
  40. Singer EA (1988) Transmitter release from brain slices elicited by single pulses: a powerful method to study presynaptic mechanisms. Trends Pharmacol Sci 9:274–276CrossRefGoogle Scholar
  41. Starke K (1987) Presynaptic α-autoreceptors. Rev Physiol Biochem Pharmacol 107:73–146CrossRefGoogle Scholar
  42. 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. Naunyn-Schmiedeberg's Arch Pharmacol 285:133–150CrossRefGoogle Scholar
  43. Starke K, Göthert M, Kilbinger H (1989) Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev 69:864–989CrossRefGoogle Scholar
  44. Steppeler A, During C, Hedler L, Starke K (1982) Effect of amezinium on the release and catabolism of 3H-monoamines in brain slices. Biochem Pharmacol 31:2395–2402CrossRefGoogle Scholar
  45. Wacber 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. Naunyn-Schmiedeberg's Arch Pharmacol 337:595–601Google Scholar
  46. Waldmeier PC, Williams M, Baumann PA, Bischoff S, Sills MA, Neale RF (1988) Interactions of isamoltane (CGP 361 A), an anxiolytic phenoxypropanolamine derivative, with 5-HT1 receptor subtypes in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 337:609–620Google Scholar
  47. Waud DR (1975) Analysis of dose-response curves. In: Daniel EE, Paton DM (eds) Methods in pharmacology, vol 3. Plenum Press, New York London, pp 471–506Google Scholar
  48. Wichmann T, Limberger N, Starke K (1989) Release and modulation of release of serotonin in rabbit superior colliculus. Neurosci 32:141–151CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • N. Limberger
    • 1
  • R. Deicher
    • 1
  • K. Starke
    • 1
  1. 1.Pharmakologisches Institut der UniversitätFreiburg i. Br.Germany

Personalised recommendations