The role of ascending noradrenergic (NA) and dopaminergic (DA) systems in intravenous self-administration of cocaine in rats was investigated by examining the effects of 6-hydroxydopamine-induced lesions of these systems on responding for the drug on a FR-1 schedule of reinforcement. Lesions of the dorsal and ventral NA bundles that reduced hippocampal-cortical NA by 96% and hypothalamic NA by 72% failed to have any effects on responding for cocaine. Lesions of the nucleus accumbens that reduced the DA content of this nucleus by 90% resulted in a significant and long-lasting (15 days) reduction in self-administration of cocaine. Apomorphine self-administration was not affected in the same animals. Identical lesions of the n accumbens had only transient (2-3 days) effects on food-reinforced operant responding, suggesting that the prolonged disruption of cocaine self-administration was not the result of motor deficits. The results are discussed with reference to the possibility that DA terminals in the n accumbens may mediate some of the positive reinforcing properties of cocaine.