AFFINITY MODULATION OF [H-3] IMIPRAMINE, [H-3] PAROXETINE AND [H-3] CITALOPRAM BINDING TO THE 5-HT TRANSPORTER FROM BRAIN AND PLATELETS

The dissociations of [H-3]imipramine, [H-3]paroxetine and [H-3]citalopram from the 5-HT (serotonin 5-hydroxytryptamine) transporter were found to be markedly influenced by several drugs, although concentrations in the mu-M range were needed. Most of these drugs attenuated the dissociation rate, i.e. increased the affinity between the ligand and the binding site. A few increased the dissociation rate however. The binding of drugs to the affinity-modulating site was specific, although of low affinity and probably changing the conformation of the high-affinity binding site, thereby changing the fit between the ligand and the interacting amino acid side-chains. Although the drugs usually affected the dissociation rates of the three ligands in the same manner, there were some which had different effects on [H-3]imipramine, [H-3]paroxetine and [H-3]citalopram. For example, 5-HT markedly attenuated the dissociation of [H-3]imipramine, had a moderate effect on [H-3]paroxetine and very little effect on [H-3]citalopram dissociation. This indicates that the three ligands are bound to different domains on the 5-HT transporter. [H-3]Citalopram dissociation from human brain and rat brain were differently affected by several drugs. Indalpine augmented the dissociation rate of the [H-3]citalopram 5-HT transport complex in human brain but attenuated it in rat brain, thus revealing a species difference of the 5-HT transporter.