5-HT receptor subtypes outside the central nervous system. Roles in the physiology of the gut

5-Hydroxytryptamine (5-HT) receptors have been analyzed and related to potential roles played by 5-HT in the physiology of the enteric nervous system (ENS). Three subtypes of 5-HT receptor--5-HT1P, 5-HT3, and 5-HT1A--have been found on enteric neurons. Receptors have been identified by intracellularly recording the electrical activity of enteric neurons and by studying the binding of radioligands and polyclonal anti-idiotypic antibodies raised against antibodies to 5-HT. Radioligand binding has been assessed by rapid filtration and by radioautography. 5-HT1P receptors mediate slow depolarizations of myenteric neurons that are associated with a closure of K+ channels. These responses can be inhibited by N-acetyl-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP) and by the substituted benzamide, BRL 24924. 5-HT1P-like responses can be mimicked by 5- and 6-hydroxyindalpine, by another substituted benzamide, the S stereoisomer of zacopride, and by anti-idiotypic antibodies. 5-HT1P receptors can be labeled by 3H-5-HT and 3H-5-hydroxyindalpine with high affinity and are located on neurons of both enteric plexuses and on processes of intrinsic neurons in the gastrointestinal mucosa. A similar distribution of binding sites for anti-idiotypic antibodies is revealed by immunocytochemistry. Excitatory postsynaptic potentials (EPSPs) mediated by 5-HT are abolished by 5-HT1P antagonists. Blockade of 5-HT1P receptors is accompanied by acceleration of the rate of gastric emptying. Mucosal application of cholera toxin activates enteric neurons in both plexuses; this action is blocked by 5-HT1P or 5-HT3 antagonists and by anti-idiotypic antibodies. 5-HT3 receptors are responsible for fast depolarizations associated with increased membrane conductance. These responses are antagonized by ICS 205-930 and mimicked by 2-methyl-5-HT and anti-idiotypic antibodies. 5-HT1A receptors have been reported to mediate hyperpolarizing responses associated with a rise in membrane conductance. Hyperpolarizing responses are also elicited by the 5-HT1A agonists, 8-hydroxy-di-n-propylaminotetralin (8-OH-DPAT) and 5-carboxyamidotryptamine. It is proposed that 5-HT1P receptors and perhaps 5-HT3 receptors are involved in initiating the peristaltic reflex and in regulating gastric emptying. No physiologic role has yet been identified for 5-HT1A receptors in the ENS.