In this study the mechanism by which histamine and H1 and H2 agonists evoked an overflow of radioactivity from rat vasa deferentia preloaded with [3H]noradrenaline was investigated. The overflow evoked by the various agonists was unaffected by the presence of such receptor antagonists as propranolol, phentolamine, cimetidine, or scopolamine. On the other hand, the overflow evoked by all agonists except dimaprit was inhibited by mepyramine and by two well-known neuronal uptake inhibitors, cocaine and desipramine. The inhibition by mepyramine has been attributed to its effect on the neuronal uptake process. Metabolic profile studies showed that 3,4-dihydroxyphenylglycol (DOPEG) was the major constituent in the evoked overflow caused by histamine, 2-methylhistamine, 4-methylhistamine, and dimaprit and that the overflow evoked by 2-pyridylethylamine and 2-thiazolylethylamine consisted predominantly of unchanged noradrenaline. Based on these findings, it is concluded that all of the agonists tested evoke noradrenaline release intraneuronally by entering the adrenergic nerve terminals. While dimaprit might enter by passively diffusing into the adrenergic nerves, other agonists seem to use the neuronal uptake process. Noradrenaline released intraneuronally is subsequently degraded by neuronal monoamine oxidase to form DOPEG. However, there are qualitative and quantitative differences in the metabolic profile of the overflow evoked by various agonists. It is suggested that these differences could arise from their additional properties, such as their effect on the neuronal uptake process and (or) their ability to act as substrate for neuronal monoamine oxidase.