This study describes a depolarizing action of 5-hydroxytryptamine (5-HT) on rabbit isolated preganglionic cervical sympathetic nerves using an extracellular recording technique. From cumulative concentration-response curves for 5-HT (1 mumol/l-1 mmol/l), the mean maximal depolarization was shown to be 277 +/- 32 microV and EC50 was 9.4 mumol/l (6.5-13.6 mumol/l, geometric mean, 95% confidence limits, n = 42). The responses to 5-HT displayed marked tachyphylaxis. When cumulative concentration-response curves to 5-HT and 2-methyl-5-HT were determined in the same preparations (n = 4), the mean maximal response to 5-HT was 519 +/- 167 microV, EC50 32.2 mumol/l (8.8-118 mumol/l) and the mean maximal response to 2-methyl-5-HT was 317 +/- 63 microV, EC50 35.1 mumol/l (12.9-95.5 mumol/l, geometric means, 95% confidence limits). The action of selective 5-HT antagonists was tested on repeated cumulative concentration-response curves to 5-HT. Neither methiothepin (0.1-1 mumol/l, n = 3) nor ketanserin (0.1-1 mumol/l, n = 3) had an action on 5-HT responses. The selective 5-HT3 antagonists MDL 72222, ICS 205-930 and SDZ 206-830 were all potent antagonists of the 5-HT depolarizations. The action of these antagonists was quantified by determining the apparent pA2 from the dose ratios and a Schild plot.(ABSTRACT TRUNCATED AT 250 WORDS)