Tricyclic Antidepressant Agents. I. Comparison of the Inhibition of the Uptake of 3H‐Noradrenaline and 14C‐5‐Hydroxytryptamine in Slices and Crude Synaptosome Preparations of the Midbrain‐Hypothalamus Region of the Rat Brain

: The simultaneous uptake of 3H-I-noradrenaline (NA) and 14C-5-hydroxytryptamine (5-HT) in slices from the midbrain-hypothalamus region of the rat brain was compared with the corresponding uptake in crude synaptosome preparations of the same brain region. In both preparations the uptake of the two amines was selective at the concentration used (1 x 10-7 M or lower). The KM values for the amines (NA: 2 x 10-7 M in synaptosomes and 5 x 10-7 M in slices; 5-HT: 8 x 10-8 M in synaptosomes and 6 x 10-7 M in slices) and the inhibitory concentrations (IC50) of the antidepressant agents were lower in the synaptosome experiments than in the slices experiments. Moreover the order of the inhibitory activities differed between the two preparations. In the slices experiments the NA uptake was inhibited most markedly by desipramine followed by imipramine > chlorimipramine = nortriptyline ≥ amitriptyline ≥ chlordesipramine whereas in the synaptosome experiments the order was desipramine > nortriptyline ≥ chlordesipramine ≥ imipramine > amitriptyline ≥ chlorimipramine. For the 5-HT uptake in slices the order of activity was: chlorimipramine > imipramine ≥ amitriptyline ≥ chlordesipramine = desipramine ≥ nortriptyline whereas in the synaptosome preparations the order was: chlorimipramine > imipramine ≥ amitriptyline ≥ chlordesipramine > nortriptyline = desipramine. The role of protein binding and diffusion barriers in the causation of the difference in the results obtained with the two preparations is discussed.