Enteric receptors for 5-hydroxytryptamine.

[3H]5-hydroxytryptamine [( 3H]5-HT) was used as a radioligand to study enteric 5-HT receptors. Membranes were derived from preparations of longitudinal muscle with adherent myenteric plexus and of mucosa-submucosa dissected from guinea pig and rabbit small intestines. Filtration and radioautographic analyses were used. Specific [3H]5-HT binding was found in both preparations. Binding was saturable and dissociable with equilibrium dissociation constants (Kd) of 2.7 and 1.4 nM, respectively. A kinetic estimate of Kd (1.5 nM) was similar to that determined by saturation analysis and the Hill coefficient approximated unity. Ring-hydroxylation of indoles was found to be a requirement for antagonism of [3H]5-HT binding. On the other hand, substitutions could be made in the aliphatic side chain of tryptamines without destroying the affinity of analogues for the binding sites. The inability of antagonists to displace [3H]5-HT indicated that the binding sites were not muscarinic or nicotinic receptors, alpha- or beta-adrenoceptors, H1 or H2 histamine receptors, dopamine receptors or either the S1 or S2 types of 5-HT receptor that have been found in the brain. Frozen section dry-mount radioautography revealed the [3H]5-HT binding sites to be located in ganglia of the myenteric plexus and at the boundary between the mucosa and submucosa. The similarity between the structure-activity requirements for affinity at the [3H]5-HT binding sites and activation of neural or M receptors for 5-HT in the gut, as well as the characteristics and location of the binding sites suggests that they are enteric neural receptors for 5-HT.