The possible central regulation of cardiovascular system by serotoninergic neurones was investigated in rats by using a cross-circulated head preparation. Intracarotid injections of serotonin (5-HT, 0.1-10 micrograms) consistently produced neurally mediated vasodepression in the recipient body. Although intravenous injections of 5-HT (0.1-1 micrograms) caused similar depressor responses, larger doses (5-10 micrograms) caused biphasic responses, consisting of vasodepression followed by a sustained pressor response. Despite the biphasic blood pressure responses, sympathetic nerve activity was consistently reduced by the intravenous 5-HT. Bilateral vagotomy abolished the vasodepressor responses to intravenous injections of 5-HT (10 micrograms) and made the responses purely pressor, but the vasodepressor responses to intracarotid injections of 5-HT (10 micrograms) were largely unaffected. Following destruction of central noradrenergic neurones by intracerebroventricular injections of 6-hydroxydopamine, the vasodepressor responses to intracarotid 5-HT (1-10 micrograms), but not to the intravenous 5-HT, were significantly reduced. These results suggest that intravenous injections of 5-HT reduce nerve activity by affecting the reflex mechanism via the vagus nerves. On the other hand, the vasodepression and reduction of the nerve activity by the intracarotid injections appears to be of central origin, and the vasodepression could be mediated via noradrenergic mechanisms in the brain.