The 5-hydroxytryptamine 5-HT_1D receptor subtype is negatively coupled to adenylate cyclase in calf substantia nigra

1) The possibility was explored that the recently defined 5-HT_1D binding sites could be negatively coupled to adenylate cyclase in calf substantia nigra. 2) 5-HT inhibited forskolin-stimulated adenylate cyclase activity in a concentration-dependent manner (EC₅₀ valu e = 24.0 nmol/l, E_max = 22.7% inhibition) in the presence of GTP (10 μmol/l), which was required for this inhibitory effect. 3) The following 5-HT receptor agonists inhibited adenylate cyclase activity (in decreasing order of potency): 5-carboxamidotryptamine > 5-HT > 5-methoxytryptamine > 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole (RU 24969) ≥ N₁N-dipropyl-5-carboxamidotryptamine > 8-hydroxy-2(di-n-propylamino)-tetralin (8OH-DPAT) > buspirone > ipsapirone; the latter two compounds apparently behaved as partial agonists. 4) Other compounds displaying agonist activity in this system were: metergoline > methysergide ≥ rauwolscine ≥ cyanopindolol > yohimbine > (±)-4(3-tert-butyl-amino 2-hydroxypropoxy)-indol-2 carbonic acid isopropylester (21-009) > corynanthine. 5) Methiothepin, mianserin and spiperone displaced the concentration-effect curve of 5-HT to the right without depressing the E_max value. The same held true for the partial agonists ipsapirone, buspirone and corynanthine. 6) The rank order of potency of agonists as well as of antagonists in this system was in full agreement with their affinities at 5-HT_1D binding site. A highly significant correlation was found between both parameters (r = 0.94, P = 0.0001). 7) The results strongly support the contention that 5-HT_1D binding sites are negatively coupled to adenylate cyclase in calf substantia nigra.