Multiple 5-HT receptors in the guinea-pig superior cervical ganglion.
1. We have studied the pharmacology of the depolarization by 5-hydroxytryptamine (5-HT) of the guinea-pig isolated superior cervical ganglion (SCG) using the grease-gap technique. We studied the effects of selective and non-selective antagonists on the responses to 5-HT and other 5-HT receptor agonists. 2. We have extended the pharmacology of the 5-HT3 receptor in this preparation by studying the effects of granisetron, BRL 46470 and mianserin on the concentration-response curve (CRC) to 2-methyl-5-HT. As with other 5-HT3 receptor antagonists, these compounds exhibited a lower affinity for guinea-pig 5-HT3 receptors than for rat 5-HT3 receptors. 3. We have confirmed that low concentrations of 5-HT (< or = 1 microM) mediate ketanserin-sensitive responses and higher concentrations of 5-HT also recruit 5-HT3 receptors. The responses to low concentrations of 5-HT were antagonized by low concentrations of ketanserin, spiperone, mianserin, DOI and LSD indicating probably mediation by 5-HT2A receptors. At high concentrations, the hallucinogen, DOI, but not LSD, evoked a ketanserin-sensitive depolarization. 4. Although mianserin could bind to the 5-HT2A receptors in this preparation, we could not demonstrate a down-regulation of depolarizations evoked by these receptors after a 10 day oral treatment with mianserin (10 mg kg-1, daily). 5. 5-Carboxamidotryptamine (5-CT) evoked a prolonged depolarization. Although high concentrations of 5-CT (> or = microM) appeared to activate 5-HT2A receptors, lower concentrations of 5-CT evoked a response with a distinct pharmacology. After studying the action of 20 selective and non-selective 5-HT receptor ligands we believe that this response may be mediated by a novel receptor; but its pharmacology is closest to that of receptors in the 5-HT2 receptor family. Like 5-CT, 5-HT (3-300 microM) could evoke an LSD-sensitive response in the presence of the 5-HT2 receptor antagonist, ketanserin and the 5-HT3 receptor antagonist, tropisetron (all 1 microM). 6. We conclude that 5-HT activates three pharmacologically distinct receptors to depolarize the guinea-pig SCG. Low concentrations of 5-HT appear to activate 5-HT2A receptors. Higher concentrations of 5-HT also activate 5-HT3 receptors and a possible novel 5-HT receptor. The novel receptor could be a species homologue of a 5-HT2 receptor or an, as yet, unclassified 5-HT receptor.
Watkins
C J
CJ
University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford.
Newberry
N R
NR
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D008803:Mianserin / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D017783:Superior Cervical Ganglion / Q000187:drug effects* / Q000378:metabolism*
D000662:Amphetamines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D018490:Serotonin Agents; D008803:Mianserin; D012701:Serotonin; C045918:2-methyl-5-HT; C047087:5-carboxamidotryptamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine