The effect of rilmenidine (S 3341) and clonidine on the firing rate of locus ceruleus (LC) and dorsal raphe (DR) cells was studied in vivo after systemic and microiontophoretic administration. The effect of the 2 drugs was also studied in vitro on brain slices containing LC cells. Rilmenidine and clonidine inhibited the firing of LC and DR neurons. Complementary experiments performed with yohimbine and prazosin demonstrated that the effect of LC is related to an agonistic action on alpha 2 somatodendritic receptors, whereas the effect observed on DR cells is indirect. On LC cells, clonidine is 30 to 60 times as potent as rilmenidine. These observations may be related to less sedative effects of rilmenidine than of clonidine.