Evidence for two types of 5-hydroxytryptamine receptor on secretomotor neurons of the guinea-pig ileum

Summary Flat sheet preparations of the mucosa plus submucosa from the guinea-pig ileum were placed in Ussing chambers so that short circuit currrent (I_sc), an index of electrolyte movement across the mucosa, could be measured. In these preparations, 5-hydroxytryptamine (5-HT) increasesI_sc indirectly by stimulating both cholinergic and non-cholinergic secretomotor neurons. The 5-HT₃ receptor antagonist, ICS 205–930 (10^–13–10^–5 M), substantially depressed the secretory response due to 5-HT (10^–6 M), but not that produced by direct activation of muscarinic receptors on the mucosal epithelium with carbachol (10^–6 M), or by stimulation of secretomotor neurons with substance P (10^–8 M) or 1,1-dimethyl-4-phenylpiperazinium (10^–5 M). The residual response to 5-HT, after the addition of a maximally effective concentration of ICS 205–930 (10^–6 M), was further reduced by hyoscine (10^–7M). When that part of the 5-HT response attributable to the release of acetylcholine was blocked by hyoscine (10^–7M), ICS 205–930 did not further modify the response to 5-HT. The hyoscine-resistant component was, however, sustantially depressed by tetrodotoxin (3.5 × 10^–7 M). The response remaining after ICS 205–930 and hyoscine was not affected by methysergide (2 × 10^{– 5} M) or cyproheptadine (10^–7 M). We conclude that there are ICS 205–930 sensitive 5-HT receptors on cholinergic secretomotor neurons, and ICS 205–930, methysergide, and cyproheptadine insensitive 5-HT receptors on non-cholinergic secretomotor neurons.