Employing an in. vitro method adapted from Snyder and Coyle (1969) and using rat whole brain homogenate, twelve drugs (cocaine, tyramine, four tricyclic antidepressants, and six antihistamines) were studied with respect to their effects on inhibition of neuronal uptake of H-noradrenaline (NA) and on release of the amine from presynaptic nerve terminals. To distinguish between the separate actions on catecholamine release and inhibition of the uptake process, two basic procedures were used. In

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... e first, homogenate was preincu-3 bated with H-NA prior to addition of the drug in order to load the nerve endings with NA so that the effects of drugs on release could be measured. The second procedure involved preincubating homogenate with the various drugs followed by addi-3 tion of the H-NA and further incubation in order to assess the inhibitory effects of the drugs on NA uptake. From the former experiments, all drugs tested were found to produce some release of NA although tyramine was by far the most potent drug in this respect. Tripelennamine and cocaine were observed to produce the least release of the twelve drugs. Of the remaining compounds, which were significantly less potent than tyramine, the tricyclic antidepressants were generally more effective in producing release than the antihistaminics. When the potencies of these compounds were correlated with their respective lipid solubilities, only tyramine deviated greatly from the established linear relationship. This indicated that, unlike the other drugs which appeared to be causing NA release through a nonspecific mechanism related to lipophilicity, tyramine is acting by a specific mechanism, probably involving accumulation of this amine by the NA uptake mechanism followed by displacement and subsequent release of bound intracellular NA. The studies of inhibition of NA uptake again demonstrated tyramine to be the most potent of the twelve drugs although in this case it did not differ significantly from cocaine and tripelennamine. The remaining compounds also showed a de-3 creased accumulation of H-NA but were less potent than tyramine (although all drugs produced inhibition of uptake of NA' at a lower dose than that required for release of the amine). Tyramine again deviated from the linear relationship between inhibitory potency and partition coefficient, but so did cocaine and tripelennamine. Chlorpheniramine and diphenhydramine also did not seem to fit the correlation although the discrepancy was less pronounced than for the other three compounds. It thus appears that drugs such as tyramine, cocaine and tripelennamine are inhibiting accumulation of NA by a specific interaction with the neuronal uptake process, whereas the other compounds studied may be acting in a noncompetitive, nonspecific manner or with mixed effects. Only tyramine, besides blocking the uptake mechanism competitively, also appears to act as a substrate for the transport system and therefore can enter the nerve terminal to bring about direct release. Signatures of Examiners