DIMERIZATION OF 8-OH-DPAT INCREASES ACTIVITY AT SEROTONIN 5-HT1A RECEPTORS

[S-35]GTP gamma S 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 ma ximal [S-35]GTP gamma S binding response to 8-hydroxy-2-(di-n-propylam ino)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 mu M. Whereas dimerization of 8-OH-DPAT almost did not affect its potency at h 5-HT1A receptors (pEC(50): 7.4 5 and 7.40 for 8-OH-DPAT and its dimer at 30 mu M GDP), it increased e fficacy at h 5-HT1A receptors. The maximal response to the 8-OH-DPAT d imer was systematically greater than the response to 8-OH-DPAT and ide ntical 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 GD P concentration. An enhanced [S-35]GTP gamma S binding response (44 to 63% vs 8-OH-DPAT) was also observed in the hippocampus, lateral septu m, dorsal raphe and cingulate cortex of guinea-pig brain sections usin g 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 respo nses by GDP suggests that the [S-35]GTP gamma S binding responses to t hese two ligands could be mediated by different G-protein subtypes upo n activation of the 5-HT1A receptor.