Abstract: The binding of the 5‐hydroxytryptamine (5‐HT, serotonin) uptake inhibitor (3H)paroxetine to rat cortical homogenates has been characterized. The effect of tissue concentration was examined and, with 0.75 mg wet weight tissue/ml in a total volume of 1,600 μl, the binding was optimized with an apparent dissociation constant (KD) of 0.03–0.05 nM. Competition experiments with 5‐HT, citalopram, norzimeldine, and desipramine revealed a high (90%) proportion of displaceable binding that fitted a single‐site binding model. Fluoxetine and imipramine revealed, in addition to a high‐affinity (nanomolar) site, also a low‐affinity (micromolar) site representing approximately 10% of the displaceable binding. The specificity of the (3H)paroxetine binding was emphasized by the fact that 5‐HT was the only active neurotransmitter bound and that the serotonin S1 and S2 antagonist methysergide was without effect on the binding. Both 5‐HT‐ and fluoxetine‐sensitive (3H)paroxetine binding was completely abolished after protease treatment, suggesting that the binding site is of protein nature. Saturation studies with 5‐HT (100 μM) sensitive (3H)paroxetine binding were also consistent with a single‐site binding model, and the binding was competitively inhibited by 5‐HT and imipramine. The number of binding sites (Bmax) for 5‐HT‐sensitive (3H)paroxetine and (3H)imipramine binding was the same, indicating that the radioligands bind to the same sites. Lesion experiments with p‐chloroamphetamine resulted in a binding in frontal and parietal cortices becoming undetectable and a >60% reduction in the striatum and hypothalamus, indicating a selective localization on 5‐HT terminals. Together these findings suggest that (3H)paroxetine specifically and selectively labels the substrate recognition site for 5‐HT uptake in rat brain.
Journal of Neurochemistry – Wiley
Published: Jun 1, 1988
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