Pharmacological characterization of two 5-hydroxytryptamine receptors coupled to adenylate cyclase in guinea pig hippocampal membranes

Two 5-hydroxytryptamine (5-HT) receptors mediate stimulation of adenylate cyclase activity in membranes of adult guinea pig hippocampus. The two receptors were characterized with agonists and antagonists and with the aid of computerized curve-fitting procedures. Each receptor mediates about 50% of the maximal response to 5-HT. 5-HT is about 10-fold more potent in eliciting response through one cyclase-linked receptor (R(H)) than the other (R(L)). The concentrations of 5-HT that elicit half-maximal response through R(H) and R(L) are 43 ± 6 nM and 414 ± 53 nM, respectively. 5-Methoxytryptamine (5-MeOT) and 5-HT are approximately equipotent at each receptor. The agonists tryptamine and bufotenine are less potent than 5-HT at both receptors, and each is about 50-fold selective for R(H). The two receptors are best discriminated by the agonists 5-carboxamidotryptamine (5-CONH₂-T) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), both of which are selective for R(H). 5-CONH₂-T is about 7-fold more potent than 5-HT at R(H). The rank order of agonist potencies at R(H) (5-CONH₂-T > 8-OH-DPAT = 5-HT = 5-MeOT > bufotenine > tryptamine) differs from that at R(L) (5-HT = 5-MeOT > bufotenine > tryptamine = 5-CONH₂-T > 8-OH-DPAT). Spiperone acts as a simple competitive antagonist at R(H), with a dissociation constant of 20 nM but it is at least 100-fold less potent as an antagonist at R(L). The relatively low affinities of the selective 5-HT antagonists ketanserin and MDL 72222 for R(H) and R(L) indicate that neither receptor may be classified as the 5-HT₂ or as the 5-HT₃ (i.e., peripheral neuronal) type. The characteristics of R(H) suggest that it is a functional correlate of the 5-HT(1A)-binding site in brain. R(L) appears not to correspond to a known 5-HT-binding site, but it may be homologous to receptors that mediate 5-HT-stimulated adenylate cyclase activity in other systems such as infant rat colliculi. R(H) and R(L) may also mediate stimulation of adenylate cyclase activity by 5-HT in hippocampal membranes of adult rat.