Dimerization of 8-OH-DPAT increases activity at serotonin 5-HT1A receptors

[35S]GTPγS binding responses can be used to measure differences between the intrinsic activity of ligands at human 5-hydroxytrypamine-1A (h 5-HT1A) receptors expressed in recombinant cell lines. The maximal [35S]GTPγS binding response to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was lower than that to 5-HT in a recombinant C6-glial membrane preparation and dependent on the GDP concentration: it was attenuated by about 60% vs 5-HT by increasing the concentration of GDP from 0.3 to 30 and 300 μM. Whereas dimerization of 8-OH-DPAT almost did not affect its potency at h 5-HT1A receptors (pEC50: 7.45 and 7.40 for 8-OH-DPAT and its dimer at 30 μM GDP), it increased efficacy at h 5-HT1A receptors. The maximal response to the 8-OH-DPAT dimer was systematically greater than the response to 8-OH-DPAT and identical to that to 5-HT; moreover in contrast to the 8-OH-DPAT monomer, the maximal response to the dimer was unaffected by increasing the GDP concentration. An enhanced [35S]GTPγS binding response (44 to 63% vs 8-OH-DPAT) was also observed in the hippocampus, lateral septum, dorsal raphe and cingulate cortex of guinea-pig brain sections using autoradiography of 5-HT1A receptor-activated G-proteins. Hence, the 8-OH-DPAT dimer shows increased efficacy at 5-HT1A receptors compared to 8-OH-DPAT. The differential regulation of the maximal agonist responses by GDP suggests that the [35S]GTPγS binding responses to these two ligands could be mediated by different G-protein subtypes upon activation of the 5-HT1A receptor.