Korean Journal of Biological Psychiatry

Many evidences are compatible with the correlation between the inhibition of [³H] imipramine([³H]IMI) and [³H]paroxetine([³H]PAT) binding to the 5-hydroxytryptamine(5-HT) transporter complex and the 5-HT uptake of 5-HT neurons and platelets, and most antidepressants have been shown to inhibit the [³H]IMI and [³H]PAT binding and the neuronal 5-HT uptake. However, several paradoxical research findings led to doubt about the pharmacological significance of the [³H]IMI and [³H]PAT binding sites. This study was carried to clarify the correlation between the [³H]IMI and [³H]PAT binding parameters and the tissue 5-HT content or/and [³H]5-HT uptake in the rabbit platelet, which contains 40 times ad much 5-HT as that of human platelet and shows the 10 fold higher B_max of the 5-HT transporter binding to a 5-HT uptake inhibitor. The rabbits were treated for 28 days with amitriptyline(4mg/kg/day : AP), fluoxetine(0.5mg/kg/day : FO), and sertraline(0.5mg/kg/day : SA) via an Alzet osmotic pump implanted for constant infusion. The [³H]IMI binding B_max and K_d of the rabbit platelets were 6.4±1.2pmol/mg protein and 10.9±2.1nM and those in the [³H]PAT binding were 8.6±1.1pmol/mg protein and 1.6±0.3nM, respectively. AP slightly increased B_max of [³H]IMI binding and both [³H]IMI binding and [³H]PAT binding K_d, and i contrast, it slightly decreased B_max of [³H]PAT binding. FO Slightly increased K_d of both and [³H]IMI and [³H]PAT binding and slightly decreased B_max of [³H]IMI and [³H]PAT binding. SA produced the significant increase of [³H]PAT binding B_max and the slight increase of both [³H]IMI and [³H]PAT binding K_d and in contrast, it slightly decreased B_max and of [³H]IMI binding. And, the V_max and K_m of platelet [³H]5-HT uptake were 24.2±2.4pmol/10⁸ platelets/min and 3.3±0.3nM, respectively. The V_max was little affected by AP, FO, or SA, but the [³H]5-HT uptake K_m value was moderately increased by FO. However, the platelet 5-HT content was moderately decreased by all of the 5-HT uptake inhibitors used in this study. These results seem to be consistent with the allosterical and competitive interaction of 5-HT uptake inhibiting antidepressants with each other as well as 5-HT in the 5-HT transporter binding, and provide no support for the view that the potencies of 5-HT uptake inhibitors to inhibit the [³H]IMI or [³H]PAT binding with 5-HT transporter complex correlate with their antidepressant potencies.

Keywords 5-HT Uptake inhibitors;[³H]Imipramine binding;[³H]Paroxetine binding;[³H]5-HT uptake;[³H]5-HT Content.