Lack of 5-hydroxytryptamine_1A-mediated inhibition of adenylyl cyclase in dorsal raphe of male and female rats

In the rat hippocampus, 5-hydroxytryptamine (5-H7)_1A receptors couple to two independent effector mechanisms, the inhibition of adenylyl cyclase activity and the opening of a K⁺ channel. In the dorsal raphe, 5-HT_1A receptors also open K⁺ channels; however, coupling to adenylyl cyclase has not been demonstrated. In this study, the selective 5-HT_1A agonists (±)-8-hydroxy-2-(di-n-propylamino)tetralin, (R⁺)-8-hydroxy-2-(di-n-propylamino)tetralin and dipropyl-5-carboxamidotryptamine, did not inhibit forskolin-stimulated adenylyl cyclase (FSAC) activity in raphe region homogenates, although these drugs were efficacious in hippocampal homogenates. Other 5-HT_1A agonists, NAN-190, BMY-7378, buspirone and gepirone, were also ineffective in raphe region homogenates. Estrogen-treatment of ovariectomized female rats, which is known to enhance 5-HT_1A-mediated inhibition of FSAC in the hippocampus, did not promote the action of 5-HT_1A agonists. Nor did activation of 5-HT_1A receptors stimulate basal adenylyl cyclase activity in raphe homogenates as it does in the hippocampus. FSAC activity was inhibited in raphe region homogenates by activation of adenosine A₁ or γ-aminobutyric acid_B receptors or by direct activation of the inhibitory G-protein, G_i, with guaznyl-5′-6′-imidodiphosphate, indicating that the raphe homogenates have the biochemical machinery for inhibition of FSAC. High affinity binding studies showed that, in raphe homogenates, 5-HT_1A receptors were expressed at a density comparable to that of adenosine A1 receptors and that they were coupled to G-proteins. It should be noted that our failure to observe 5-HT_1A-mediated inhibition of adenylyl cyclase in the raphe does not prove that such coupling does not exist. However, a lack of 5-HT_1A receptor coupling to adenylyl cyclase in the raphe would support contentions that coupling of the 5-HT_1A receptor to adenylyl cyclase may be independent of its coupling to the K⁺ channel and that there may be distinct differences between pre- and postsynaptic 5-HT_1A receptor systems.