Dual agonist-antagonist effects of 5-hydroxytryptamine (5-HT) in the guinea pig ileum: evidence for a selective receptor desensitization effect.

The application of 5-HT to strips of whole ileum or the longitudinal muscle-myenteric plexus preparation from guinea pigs caused dose-dependent muscle contractions that were followed by relaxation to baseline tension without washing off the drug (fade). The contractile effect of a subsequent addition of 5-HT, 4 min after a priming dose of 5-HT, was markedly reduced. Increasing priming doses of 5-HT caused proportional increases in the 5-HT Emax50, up to a priming dose that completely abolished the contractile effects caused by further additions of 5-HT. The auto-blockade of the 5-HT responses was selective to drugs acting on serotonergic receptors. 5-HT did not antagonize the effects of acetylcholine, dimethylphenylpiperazinium, nicotine, histamine, prostaglandin E2, substance P or angiotensin II. N-methyl-5-HT was the most potent analogue in mimicking the effects of 5-HT to produce auto-blockade and fade of the contractile responses. Other structural analogues of 5-HT that shared the 5-HT blocking effect were 5-methoxytryptamine, 5,6-dihydroxytryptamine, and N,N-dimethyltryptamine although these compounds were considerably less potent than 5-HT as blockers or as agonists. Results suggest that fade and the auto-blockade are part of a common effect and are discussed in relation to a model of drug-induced selective receptor desensitization.