MULTIPLE 5-HT RECEPTORS IN THE GUINEA-PIG SUPERIOR CERVICAL-GANGLION

1 We have studied the pharmacology of the depolarization by 5-hydroxyt ryptamine (5-HT) of the guinea-pig isolated superior cervical ganglion (SCG) using the grease-gap technique. We studied the effects of selec tive 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-H T3 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 compou nds 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 (less than or equal to 1 mu M) mediate ketanserin-sensitive respon ses and higher concentrations of 5-HT also recruit 5-HT3 receptors. Th e responses to low concentrations of 5-HT were antagonized by low conc entrations of ketanserin, spiperone, mianserin, DOI and LSD indicating probably mediation by 5-HT2A receptors. At high concentrations, the h allucinogen, DOI, but not LSD, evoked a ketanserin-sensitive depolariz ation. 4 Although mianserin could bind to the 5-HT2A receptors in this preparation, we could not demonstrate a down-regulation of depolariza tions evoked by these receptors after a 10 day oral treatment with mia nserin (10 mg kg(-1), daily). 5 5-Carboxamidotryptamine (5-CT) evoked a prolonged depolarization. Although high concentrations of 5-CT (grea ter than or equal to 1 mu M) appeared to activate 5-HT2A receptors, lo wer concentrations of 5-CT evoked a response with a distinct pharmacol ogy. After studying the action of 20 selective and non-selective 5-HT receptor ligands we believe that this response may be mediated by a no vel receptor; but its pharmacology is closest to that of receptors in the 5-HT2 receptor family. Like 5-CT, 5-HT (3 - 300 mu M) could evoke an LSD-sensitive response in the presence of the 5-HT2 receptor antago nist, ketanserin and the 5-HT3 receptor antagonist, tropisetron (all 1 mu M). 6 We conclude that 5-HT activates three pharmacologically dist inct 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. T he novel receptor could be a species homologue of a 5-HT2 receptor or an, as yet, unclassified 5-HT receptor.