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-HT)(1A) receptors coupl e to two independent effector mechanisms, the inhibition of adenylyl c yclase activity and the opening of a K+ channel. In the dorsal raphe, 5-HT1A receptors also open K+ channels; however, coupling to adenylyl cyclase has not been demonstrated. In this study, the selective 5-HT1A agonists (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, (R(+))-8-hydro xy-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-HT1A agonists, NAN-190, BMY-7378, bus pirone and gepirone, were also ineffective in raphe region homogenates . Estrogen-treatment of ovariectomized female rats, which is known to enhance 5-HT1A-mediated inhibition of FSAC in the hippocampus, did not promote the action of 5-HT1A agonists. Nor did activation of 5-HT1A r eceptors stimulate basal adenylyl cyclase activity in raphe homogenate s as it does in the hippocampus. FSAC activity was inhibited in raphe region homogenates by activation of adenosine A(1) or gamma-aminobutyr ic acid(B) receptors or by direct activation of the inhibitory G-prote in, G(i), with guanyl-5'6'-imidodiphosphate, indicating that the raphe homogenates have the biochemical machinery for inhibition of FSAC. Hi gh affinity binding studies showed that, in raphe homogenates, 5-HT1A receptors were expressed at a density comparable to that of adenosine A, receptors and that they were coupled to G-proteins. It should be no ted that our failure to observe 5-HT1A-mediated inhibition of adenylyl cyclase in the raphe does not prove that such coupling does not exist . However, a lack of 5-HT1A receptor coupling to adenylyl cyclase in t he raphe would support contentions that coupling of the 5-HT1A recepto r to adenylyl cyclase may be independent of its coupling to the K+ cha nnel and that there may be distinct differences between pre- and posts ynaptic 5-HT1A receptor systems.