Distinct Effects of Imipramine on 5-Hydroxytryptamine Uptake Mediated by the Recombinant Rat Serotonin Transporter SERT1 |
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Authors: | Cyrille Sur Heinrich Betz Patrick Schloss |
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Affiliation: | Department of Neurochemistry, Max-Planck-Institute for Brain Research, Frankfurt am Main, Germany |
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Abstract: | Abstract: Tricyclic and nontricyclic serotonin [5-hydroxytryptamine (5-HT)] uptake inhibitors are widely used for the treatment of depression. Here, we show that both the tricyclic antidepressant imipramine and the nontricyclic antidepressant citalopram competitively inhibit 5-HT transport mediated by the recombinant rat 5-HT transporter SERT1. For citalopram, the concentration producing half-maximal transport inhibition was in the same order of magnitude as its K D value determined by equilibrium binding. In contrast, the inhibitory potency of imipramine was more than one order of magnitude lower than its K D value. Our data are consistent with low-affinity imipramine binding occurring at or close to the substrate recognition site, which also binds citalopram. Occupation of the high-affinity imipramine binding site on SERT1 did not affect 5-HT transport but allosterically displaced citalopram from the substrate recognition site. Consequently, low concentrations of imipramine partially protected 5-HT transport from citalopram inhibition. This protection was only observed in the presence of Na+ because high-affinity imipramine binding is strictly sodium-dependent. Thus, depending on which of its binding sites on SERT1 is occupied, imipramine may exert distinct effects on 5-HT uptake mediated by the recombinant rat 5-HT transporter. |
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Keywords: | Serotonin Uptake Antidepressant binding Tricyclic antidepressants Selective serotonin uptake inhibitors |
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