The effects of intracisternal clonidine (0.04, 0.2, and 1.0 microgram/kg) and of alpha-methyldopa (alpha-MD; 400 micrograms/kg) on mean arterial pressure (MAP) and heart rate (HR) were studied in conscious rabbits before, and 7 and 14 days after, intracisternal injection of (a) vehicle, (b) 6-hydroxydopamine (6-OHDA; 600 micrograms/kg), or (c) 5,6-dihydroxytryptamine (5,6-DHT; 633 micrograms/kg) (n = 6 per group). In the initial control experiment clonidine and alpha-MD produced similar falls in MAP and HR in each group; there was also good reproducibility of responses in vehicle-treated rabbits on the 3 experimental days. But after 6-OHDA or 5,6-DHT administration the circulatory effects of clonidine and alpha-MD were markedly attenuated. On day 14 after injection of 6-OHDA, the clonidine-induced falls in MAP and HR averaged 38 and 18%, respectively, of the control responses (p less than 0.001). On day 14 after 5,6-DHT administration, the falls in MAP and HR after clonidine administration were reduced to 27 and 13% of control, respectively (p less than 0.01), while the corresponding responses after alpha-MD administration were 39 and 61% of control (p less than 0.05). Neurochemical findings suggest that 6-OHDA affected noradrenergic (NA), dopaminergic (DA), but not serotonergic (5HT) neurons, and that 5,6-DHT affected 5HT but not NA and DA neurons. We conclude that the circulatory effects of clonidine and alpha-MD are mediated through both central NA and 5HT neurons.