Examination of the relationship between the uptake system for 5-hydroxytryptamine and the high-affinity [3H]imipramine binding site--I. Inhibition by drugs.

The relationship between the binding site for imipramine and the uptake system for 5-hydroxytryptamine was examined. This was determined from the interaction between various drugs (including tricyclic antidepressants) and the high affinity accumulation of [3H]5-hydroxytryptamine in cortical synaptosomes from the rat, and with the high affinity binding of [3H]imipramine to cortical membranes of the rat. Imipramine and clomipramine, but not desipramine, were potent inhibitors of both binding of [3H]imipramine and the uptake of [3H]5-hydroxytryptamine. However, ouabain, panuramine and 5-hydroxytryptamine itself, all inhibited the binding of [3H]imipramine only at concentrations greater than those required to inhibit the uptake of [3H]5-hydroxytryptamine. Kinetic analysis revealed that inhibitors of the uptake system for 5-hydroxytryptamine produced inhibition by different mechanisms, but this did not account for their differential potency against uptake and binding. It is concluded that the binding site for [3H]imipramine and the uptake site for 5-HT are not directly linked and that drugs may inhibit the uptake of 5-HT at sites other than the binding site for [3H]imipramine.