Summary
-
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.
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.
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.
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.
In conclusion, the evidence indicates that the presynaptic 5-HT autoreceptor belongs to the 5-HT1B receptor subtype.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
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
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
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
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
Deshmukh PP, Nelson DL, Yamamura HJ (1982) Localization of 5-HT1 receptor subtypes in rat brain by autoradiography. Fed Proc 41:1338
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
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
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
Feldman HA (1972) Mathematical theory of complex ligand-binding systems at equilibrium: some methods of parameter fitting. Anal Biochem 48:317–338
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
Gaddum JH, Picarelli ZP (1957) Two kinds of tryptamine receptor. Br J Pharmacol Chemother 12:323–328
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
Göthert M (1982) Modulation of serotonin release in the brain via presynaptic receptors. Tr Pharmacol Sci 3:437–440
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
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
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
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
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
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
Héry F, Ternaux JP (1981) Regulation of release processes in central serotoninergic neurons. J Physiol (Paris) 77:287–301
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
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
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
Martin LL, Sanders-Bush E (1982b) The serotonin autoreceptor: antagonism by quipazine. Neuropharmacology 21:445–450
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
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
Middlemiss DN (1984b) Stereoselective blockade at [3H]5-HT binding sites at the 5-HT autoreceptor by propranolol. Eur J Pharmacol 101:289–293
Middlemiss DN (1985) β-Adrenoceptor antagonists and blockade of the 5-HT autoreceptor in rat frontal cortex. Br J Pharmacol 84:189P
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
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
Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. 1. Serotonin-1 receptors. Brain Res 346:205–230
Pazos A, Engel G, Palacios JM (1985) β-adrenoceptor blocking agents recognize a subpopulation of serotonin receptors in brain. Brain Res 343:403–408
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
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
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
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
Peroutka SJ, Lebovitz RM, Snyder SH (1981) Two distinct central serotonin receptors with different physiological functions. Science 212:827–829
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
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
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
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
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
Starke K (1981) Presynaptic receptors. Annu Rev Pharmacol Toxicol 21:7–30
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
Author information
Authors and Affiliations
Additional information
M. Göthert was supported by a grant of the “Deutsche Forschungsgemeinschaft”.
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00633189