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A series of eight substrate molecules (substituted phenethylamines, guanethidine, and bretylium) had slightly less affinity for striatal than for hypothalamic synaptosomal uptake receptors as judged by ratios of striatal (s) to hypothalamic (h) IC50 values (s/h average = 3.9; range 2.0--6.0). Catecholamine uptake in striatum was very insensitive to tricyclic antidepressant inhibitors, whereas catecholamine uptake in hypothalamus was very sensitive to these agents (s/h average = 233; range 24--570). By way of contrast with both the substrates and the tricyclic inhibitors, the inhibitors with less rigidly fixed rings or analogous groups (deoxypipradrol, methylphenidate, cocaine) were potent in both brain preparations (s/h average = 1.2; range 0.6--2.3). It is concluded that the rings of nontricyclic inhibitors are able to bind to appropriate hydrophobic binding groups in both receptors, that these receptive groups have different topography in striatum and in hypothalamus, and that the topography in the striatum is incompatible with binding tricyclic systems. The data also indicate that there is great similarity, if not identity, in the receptive area for substrates in striatum and hypothalamus. Although the substrates and inhibitors bind to some groups in common in this substrate receptive area, it is the surrounding hydrophobic molecular environment that is clearly different and permits the phenomenon of selective blockade with drugs.