Magnitude of 5-HT1B and 5-HT1A receptor activation in guinea-pig and rat brain: evidence from sumatriptan dimer-mediated [S-35]GTP gamma S binding responses

The present study reports on G-protein activation by recombinant 5-HT recep tors and by native 5-HT1A and 5-HT1B receptors in guinea-pig and rat brain using agonist-stimulated [S-35]GTP gamma S binding responses mediated by a new 5-HT ligand, a dimer of sumatriptan, Dimerization of sumatriptan increa sed the binding affinity for h 5-HT1B (pK(i): 9.22 vs. 7.79 for sumatriptan ), h 5-HT1D (9.07 vs. 8.08) and also h 5-HT1A receptors (7.80 vs. 6.40), wh ile the binding affinity for h 5-ht(1E) (6.67 vs. 6.19) and h 5-ht(1F) (7.3 7 vs. 7.78) receptors was not affected. Sumatriptan dimer (10 mu M) stimula ted [S-35]GTP gamma S binding mainly in the superficial gray layer of the s uperior colliculi, hippocampus and substantia nigra of guinea-pig and rat c oronal brain sections. This fits with the labelling by the 5-HT1B/1D recept or antagonist [H-3] GR 125743, The observed [S-35]GTP gamma S binding respo nses in the substantia ni,ara are likely to be mediated by stimulation of t he 5-HT1B receptor subtype, since they were antagonized by the 5-HT1B inver se agonist SE 224289 (10 mu M), and not by the 5-HT2A/1D antagonist ketanse rin (10 mu M). Quantitative assessment of the [S-35]GTP gamma S binding res ponses in the substantia nigra of rat showed highly efficacious responses f or both sumatriptan dimer and its monomer. In contrast, less efficacious ag onist responses (51 +/- 10% and 35 +/- 13%, respectively) were measured in the guinea-pig substantia nigra. This may suggest that the G-protein coupli ng efficacy of 5-HT1B receptors is different between the substantia nigra o f both species. In addition, the sumatriptan dimer also activated guinea-pi g and rat hippocampal 5-HT1A receptors with high efficacy in contrast to su matriptan. Therefore, dimerization of sumatriptan can be considered as a ne w approach to transform a partial 5-HT1A agonist into a more efficacious ag onist. In conclusion, the sumatriptan dimer stimulates G-protein activation via 5-HT1B receptors besides 5-HT1A receptors in guinea-pig and rat brain. The magnitude of the 5-HT1B receptor responses is superior for sumatriptan and its dimer in rat compared to guinea-pig substantia nigra, (C) 1999 Els evier Science B.V. All rights reserved.