Using immunohistochemical labeling, a dense noradrenergic innervation was observed within the wall of the sheep middle cerebral artery, but there was no evidence of serotoninergic nerves. Following preincubation with 5-hydroxytryptamine (5-HT), immunoreactivity to 5-HT was observed in nerve fibers, which appeared to be a consequence of uptake into noradrenergic nerves. Radiolabeled uptake studies provided evidence for the existence of two neuronal uptake mechanisms for 5-HT: one that was selectively inhibited by citalopram and one that was selectively inhibited by desipramine. The desipramine-sensitive mechanism had a greater affinity for noradrenaline than 5-HT, and desipramine caused a greater degree of inhibition of 5-HT uptake than citalopram. This study shows that, in the sheep middle cerebral artery, 5-HT is taken up into noradrenergic nerves by two distinct uptake mechanisms.