The metabolism of 3H-norepinephrine (3H-NE) released by different frequencies of nerve stimulation was studied in the perfused cat spleen after labeling the endogenous stores with (-)-3H-NE. For a wide range of frequencies of stimulation, unmetabolized 3H-NE represented between 50 and 60% of the total increase in outflow of radioactivity elicited by nerve stimulation. The deaminated glycol, 3,4-dihydroxyphenylglycol (3H-DOPEG), was the main metabolite of 3H-NE released by nerve stimulation. When the increase in outflow of radioactivity was analyzed for the samples collected during nerve stimulation, there was a progressive decrease in the fraction of 3H-NE released which was collected as 3H-metabolites as the frequency of stimulation was increased from 0.5 to 5 Hz. For the samples collected in the poststimulation period, there was no frequency dependence in the metabolism of the released transmitter: approximately 75% of the total overflow of radioactivity was accounted for by the 3H-NE metabolites, particularly 3H-DOPEG. The time course of the metabolism of 3H-NE released by nerve stimulation revealed that 3H-DOPEG formation was rather small during stimulation and that it increased sharply in the poststimulation samples. The selective increase in 3H-DOPEG formation in the poststimulation period is compatible with the view that neuronal uptake of the released transmitter might be increased immediately after nerve stimulation. Inhibition of neuronal uptake by cocaine or by phenoxybenzamine prevented 3H-DOPEG formation from 3H-NE released by nerve stimulation. Yet, in the presence of cocaine, the fractional release of total radioactivity per shock was not increased at either 1, 5 or 30 Hz. These results support the view that a large fraction of the 3H-NE released by stimulation which is recaptured by nerve endings is metabolized to 3H-DOPEG rather than stored for subsequent reuse. The extensive conversion to 3H-DOPEG of 3H-NE released by nerve stimulation suggests that there may be a difference between the process of neuronal uptake under resting conditions and that which operates under conditions of nerve stimulation. This difference may be related to the concentration of the transmitter achieved in the synaptic gap in each experimental condition. Under resting conditions and during perfusion with low concentrations of NE, neuronal uptake in the perfused cat spleen is coupled with vesicular storage. On the other hand, when the extracellular concentration of NE is increased as a result of nerve stimulation, neuronal uptake of NE appears to be coupled with presynaptic metabolism through monoamine oxidase and aldehyde reductase.