Skip to main content
SpringerLink
Log in

Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

  1. 1.

    In rat brain cortex slices preincubated with [3H]5-HT, the potencies of 17 5-HT receptor agonists to inhibit the electrically evoked3H overflow and the affinities of 13 antagonists (including several β-adrenoceptor blocking agents) to antagonize competitively the inhibitory effect of unlabelled 5-HT on evoked3H overflow were determined.

  2. 2.

    The affinities of the compounds for 5-HT1B and 5-HT2 binding sites in rat brain cortex membranes (labelled by [125I]cyanopindolol = [125I]-CYP in the presence of 30 μmol/l isoprenaline and [3H]ketanserin, respectively), for 5-HT1A binding sites in pig and rat brain cortex membranes (labelled by [3H]8-hydroxy-2-(di-n-propylamino)tetralin = [3H]8-OH-DPAT) and for 5-HT1C binding sites in pig choroid plexus membranes (labelled by [3H]mesulergine) were also determined. The affinities of the drugs for the various 5-HT recognition sites ranged over 4–5 log units (the functional experiments revealed the same range of differences between the drugs).

  3. 3.

    There were no significant correlations between the affinities of the drugs at 5-HT1C and 5-HT2 binding sites and their potencies or affinities, determined for the 5-HT autoreceptors. In contrast, significant correlations were found between the potencies or affinities of the drugs for the autoreceptors and their affinities at 5-HT1A or 5-HT1B binding sites; the best correlations were obtained with the 5-HT1B binding site.

  4. 4.

    Some of the drugs investigated were not included in the correlation since their agonistic or antagonistic effects on the autoreceptors were weak and pEC30 or apparent pA2 values could not be determined (<5.5). Among these drugs, 8-OH-DPAT, TVX Q 7821 (2-(4-(4-(2-pyrimidin-yl)-1-piperazinyl)-butyl)-1,2-benzisothiazol-3(2H)one-1,1-dioxide) and spiperone showed a very low affinity for 5-HT1B binding sites (pKD<5.3), but a high affinity for 5-HT1A binding sites (pKD>7.2).

  5. 5.

    In conclusion, the evidence indicates that the presynaptic 5-HT autoreceptor belongs to the 5-HT1B receptor subtype.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Baumann PA, Waldmeier PC (1981) Further evidence for negative feedback control of serotonin release in the central nervous system. Naunyn-Schmiedeberg's Arch Pharmacol 317:36–43

    Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Google Scholar 

  • Classen K, Göthert M, Schlicker E (1984) Effects of DU 24565 (6-nitroquipazine) on serotoninergic and noradrenergic neurones of the rat brain and comparison with the effects of quipazine. Naunyn-Schmiedeberg's Arch Pharmacol 326:198–202

    Google Scholar 

  • De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J Biol Chem 255:7108–7117

    Google Scholar 

  • Deshmukh PP, Nelson DL, Yamamura HJ (1982) Localization of 5-HT1 receptor subtypes in rat brain by autoradiography. Fed Proc 41:1338

    Google Scholar 

  • Dompert WU, Glaser T, Traber J (1985)3H-TVX Q 7821: identification of 5-HT1 binding sites as target for a novel putative anxiolytic. Naunyn-Schmiedeberg's Arch Pharmacol 328:467–470

    Google Scholar 

  • 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 324:116–124

    Google Scholar 

  • Engel G, Hoyer D, Kalkman HO, Wick M (1985) Pharmacological similarity between the 5-HTD receptor on the guinea pig ileum and the 5-HT2 binding site. Brit J Pharmacol 84:106P

    Google Scholar 

  • Feldman HA (1972) Mathematical theory of complex ligand-binding systems at equilibrium: some methods of parameter fitting. Anal Biochem 48:317–338

    Google Scholar 

  • Fozard JR (1983) Functional correlates to 5-HT1 recognition sites TIPS 288-289

  • 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 experimental pharmacology. Catecholamines, vol XXXIII. Springer, Berlin Heidelberg New York, pp 283–333

    Google Scholar 

  • Gaddum JH, Picarelli ZP (1957) Two kinds of tryptamine receptor. Br J Pharmacol Chemother 12:323–328

    Google Scholar 

  • Göthert M (1980) Serotonin-receptor-mediated modulation of Ca2+-dependent 5-hydroxytryptamine release from neurones of the rat brain cortex. Naunyn-Schmiedeberg's Arch Pharmacol 314:223–230

    Google Scholar 

  • Göthert M (1982) Modulation of serotonin release in the brain via presynaptic receptors. Tr Pharmacol Sci 3:437–440

    Google Scholar 

  • Göthert M (1985) Effects of 5-hydroxytryptamine at presynaptic and neural sites. In: Bevan JA et al. (eds) Vascular neuroeffector mechanisms. Elsevier, Amsterdam, pp 315–320

    Google Scholar 

  • Göthert M, Schlicker E (1983) Autoreceptor-mediated inhibition of3H-5-hydroxytryptamine release from rat brain cortex slices by analogues of 5-hydroxytryptamine. Life Sci 32:1183–1191

    Google Scholar 

  • Göthert M, Weinheimer G (1979) Extracellular 5-hydroxytryptamine inhibits 5-hydroxytryptamine release from rat brain cortex slices. Naunyn-Schmiedeberg's Arch Pharmacol 310:93–96

    Google Scholar 

  • 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 317:199–203

    Google Scholar 

  • Gozlan H, El Mestikawy S, Pichat L, Glowinski J, Hamon M (1983) Identification of presynaptic serotonin autoreceptors using a new ligand:3H-PAT. Nature 305:140–142

    Google Scholar 

  • 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)tetralin] in the rat brain. Eur J Pharmacol 100:263–276

    Google Scholar 

  • Héry F, Ternaux JP (1981) Regulation of release processes in central serotoninergic neurons. J Physiol (Paris) 77:287–301

    Google Scholar 

  • Hoyer D, Engel G, Kalkman HO (1985a) Characterization of the 5-HT1B recognition site in rat brain: binding sudies with (−)[125I]iodocyanopindolol. Eur J Pharmacol (in press)

  • Hoyer D, Engel G, Kalkman HO (1985b) Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes. Radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (−)[125I]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin. Eur J Pharmacol (in press)

  • Langer SZ, Moret C (1982) Citalopram antagonizes the stimulation by lysergic acid diethylamide of presynaptic inhibitory serotonin autoreceptors in the rat hypothalamus. J Pharmacol Exp Ther 222:220–226

    Google Scholar 

  • Leysen JE, Niemegeers CJE, Van Nueten JM, Laduron PM (1982) [3H]Ketanserin (R41468), a selective3H-ligand for serotonin2 receptor binding sites. Binding properties, brain distribution and functional role. Mol Pharmacol 21:301–314

    Google Scholar 

  • Martin LL, Sanders-Bush E (1982a) 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 321:165–170

    Google Scholar 

  • Martin LL, Sanders-Bush E (1982b) The serotonin autoreceptor: antagonism by quipazine. Neuropharmacology 21:445–450

    Google Scholar 

  • Middlemiss DN (1982) Multiple 5-hydroxytryptamine receptors in the central nervous system of the rat. In: Belleroche J, de (ed) Presynaptic receptors: mechanisms and functions. Ellis Horwood, Chichester, pp 46–74

    Google Scholar 

  • Middlemiss DN (1984a) 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 327:18–22

    Google Scholar 

  • Middlemiss DN (1984b) Stereoselective blockade at [3H]5-HT binding sites at the 5-HT autoreceptor by propranolol. Eur J Pharmacol 101:289–293

    Google Scholar 

  • Middlemiss DN (1985) β-Adrenoceptor antagonists and blockade of the 5-HT autoreceptor in rat frontal cortex. Br J Pharmacol 84:189P

    Google Scholar 

  • Middlemiss DN, Fozard JR (1983) 8-Hydroxy-2-(di-n-propylamino)-tetralin discriminates between subtypes of the 5-HT1-recognition site. Eur J Pharmacol 90:151–153

    Google Scholar 

  • Nelson DL, Schnellmann R, Smit M (1983)3H-Serotonin binding sites: Pharmacological and species differences. In: Segawa T, Yamamura HI, Kurijama K (eds) Molecular pharmacology of neurotransmitter receptors. Raven Press, New York, pp 103–114

    Google Scholar 

  • Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. 1. Serotonin-1 receptors. Brain Res 346:205–230

    Google Scholar 

  • Pazos A, Engel G, Palacios JM (1985) β-adrenoceptor blocking agents recognize a subpopulation of serotonin receptors in brain. Brain Res 343:403–408

    Google Scholar 

  • Pazos A, Hoyer D, Palacios JM (1984a) Mesulergine, a selective serotonin-2 ligand in the rat cortex, does not label these receptors in porcine and human cortex: evidence for species differences in brain serotonin-2 receptors. Eur J Pharmacol 106:531–538

    Google Scholar 

  • Pazos A, Hoyer D, Palacios JM (1984b) The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. Eur J Pharmacol 106:539–546

    Google Scholar 

  • Pedigo NW, Yamamura HJ, Nelson DL (1981) Discrimination of multiple [3H]-5-hydroxytryptamine binding sites by neuroleptic spiperone in rat brain. J Neurochem 36:220–226

    Google Scholar 

  • Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: Differential binding of [3H]-5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]-spiroperidol. Mol Pharmacol 16:687–699

    Google Scholar 

  • Peroutka SJ, Lebovitz RM, Snyder SH (1981) Two distinct central serotonin receptors with different physiological functions. Science 212:827–829

    Google Scholar 

  • Petersen EN, Olsson SO, Squires RF (1977) Effects of 5-HT uptake inhibitors on the pressor response to 5-HT in the pithed rat. The significance of the 5-HT blocking property. Eur J Pharmacol 43:209–215

    Google Scholar 

  • Richards MH (1985) Efflux of3H-5-hydroxytryptamine from rat hypothalamic slices by continuous electrical stimulation: Frequency-dependent responses to serotonergic antagonists and 5-hydroxytryptamine. Naunyn-Schmiedeberg's Arch Pharmacol 329:359–366

    Google Scholar 

  • Schlicker E, Göthert M (1981) Antagonistic properties of quipazine at presynaptic serotonin receptors and α-adrenoceptors in rat brain cortex slices. Naunyn-Schmiedeberg's Arch Pharmacol 317:204–208

    Google Scholar 

  • Schlicker E, Göthert M, Hillenbrand K (1985) Cyanopindolol is a highly potent and selective antagonist at the presynaptic serotonin autoreceptor in the rat brain cortex. Naunyn-Schmiedeberg's Arch Pharmacol 331:398–401

    Google Scholar 

  • Snedecor GW, Cochran WG (1973) In: Snedecor GW, Cochran WG (eds) Statistic methods. Curvelinar regression, 6th edn. The Iowa State University Press, Ames, pp 447–471

    Google Scholar 

  • Starke K (1981) Presynaptic receptors. Annu Rev Pharmacol Toxicol 21:7–30

    Google Scholar 

  • Vaastra WJ, Deiman-Van Aalst WMA, Eigeman L (1981) DU 24565, a quipazine derivative, a potent selective serotonin uptake inhibitor. Eur J Pharmacol 70:195–202

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Preclinical Research, Sandoz Ltd., CH-4002, Basel, Switzerland

    G. Engel & D. Hoyer

  2. Pharmakologisches Institut der Universität Essen, Hufelandstrasse 55, D-4300, Essen 1, Federal Republic of Germany

    M. Göthert, E. Schlicker & K. Hillenbrand

Authors
  1. G. Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Göthert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Hoyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Schlicker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Hillenbrand
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

M. Göthert was supported by a grant of the “Deutsche Forschungsgemeinschaft”.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Engel, G., Göthert, M., Hoyer, D. et al. 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, 1–7 (1986). https://doi.org/10.1007/BF00633189

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00633189

Key words

Search

Navigation