5-Hydroxytryptamine-sensitive [3H]imipramine binding of protein nature in the human brain. I. Characteristics

[3H]Imipramine binding sites were characterized in the human brain by investigating the sensitivity to protease treatment, dependency on NaCl and the effects of drug inhibition. The binding was found to consist of a protease sensitive and a protease resistant fraction. These two fractions could be discriminated by 5-hydroxytryptamine (5-HT) but not desipramine. The [3H]imipramine binding discriminated by 5-HT was found to be sodium dependent. The 5-HT-sensitive [3H]imipramine binding displayed a regional variability with Bmax values ranging from 50 to 100 fmol/mg protein in neocortical areas to 400-500 fmol/mg protein in the substantia nigra and hypothalamus. The Kd values for 5-HT-sensitive [3H]imipramine binding were 1-2 nM throughout the brain. Additional [3H]imipramine binding insensitive to 5-HT, but displaceable by desipramine showed little regional variation, with the binding capacity in the hypothalamus approximating that found in cortical areas. This binding fraction was of low affinity, was not dependent on the presence of NaCl and was insensitive to protease treatment. Drug inhibition studies revealed that the addition of low concentrations of 5-HT or norzimeldine to 5-HT-sensitive [3H]imipramine binding sites produced changes in affinity, consistent with a competitive interaction. It is suggested that the 5-HT-sensitive [3H]imipramine binding may represent the substrate recognition site for 5-HT uptake in the human brain.