The 5HT(1A) receptor ligand, S15535, antagonises G-protein activation: a [S-35]GTP gamma S and [H-3]S15535 autoradiography study

4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine (S15535) is a highly selective ligand at 5-HT1A receptors. The present study compared its autoradiographi c labelling of rat brain sections with its functional actions, visualised b y guanylyl-5'-[gamma-thio]-triphosphate ([S-35]GTP gamma S) autoradiography , which affords a measure of G-protein activation. [H-3]S15535 binding was highest in hippocampus, frontal cortex, entorhinal cortex, lateral septum, interpeduncular nucleus and dorsal raphe, consisten t with specific labelling of 5-HT1A receptors. In functional studies, S1553 5 (10 mu M) did not markedly stimulate G-protein activation in any brain re gion, but abolished the activation induced by the selective 5-HT1A agonist, (+)-8-hydroxy-dipropyl-aminotetralin ((+)-8-OH-DPAT, 1 mu M), in structure s enriched in [H-3]S15535 labelling. S15535 did not block 5-HT-stimulated a ctivation in caudate nucleus or substantia nigra, regions where (+)-8-OH-DP AT was ineffective and [H-3]S15535 binding was absent. Interestingly, S1553 5 attenuated (+)-8-OH-DPAT and 5-HT-stimulated G-protein activation in dors al raphe, a region in which S15535 is known to exhibit agonist properties i n vivo [Lejeune, F., Millan, M.J., 1998. Induction of burst firing in ventr al tegmental area dopaminergic neurons by activation of serotonin (5-HT)(1A ) receptors: WAY100,635-reversible actions of the highly selective ligands, flesinoxan and S15535. Synapse 30, 172-180.]. The present data show that (i) [H-3]S15535 labels pre- and post-synaptic po pulations of 5-HT1A sites in rat brain sections, (ii) S15535 exhibits antag onist properties at post-synaptic 5-HT1A receptors in corticolimbic regions , and (iii) S15535 also attenuates agonist-stimulated G-protein activation at raphe-localised 5-HT1A receptors. (C) 1999 Elsevier Science B.V. All rig hts reserved.