Hrdina P D
Eur J Pharmacol. 1987 Jun 19;138(2):159-68. doi: 10.1016/0014-2999(87)90429-8.
Specific binding of [3H]imipramine to its recognition sites in frontal cortex and levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) as well as uptake of serotonin by crude synaptosomal (P2) fraction were determined in a group of rats chronically (for 21 days) treated with different types of antidepressant drugs: nortriptyline, fluoxetine, iprindole, phenelzine (10 mg/kg per day), maprotiline (20 mg/kg per day) and vehicle only (controls). Quantitative analysis of imipramine competition curves confirmed the existence of two classes of [3H]imipramine sites: high-affinity with IC50 and 11.2 nM and low-affinity with IC50 of 630 nM for the competing ligand. The proportion of high- and low-affinity sites was 73 +/- 4 and 26 +/- 4%, respectively. Chronic treatment with all antidepressant drugs except iprindole significantly decreased the affinity but not the proportion of high-affinity sites for imipramine. IC50 of imipramine at low-affinity sites was even more markedly increased at low-affinity sites by all treatments except for phenelzine. Fluoxetine was by far the most effective in altering the affinity of both high- and low-affinity [3H]imipramine recognition sites. Both NE and 5-HT levels were significantly enhanced only by phenelzine treatment, whereas 5-HT and 5-HIAA levels were found to be lower after fluoxetine. Kinetics of 5-HT uptake were altered significantly only in rats treated with fluoxetine: rate of 5-HT uptake (Vmax) was decreased by 43% and Km value increased from 104 to 184 nM. Changes in affinity of imipramine for its binding sites were not found to be associated with the effect of tested drugs on 5-HT levels or uptake. They may be due to adaptive alterations in physico-chemical properties of binding proteins although the presence of residual drug interfering with the binding assay cannot be excluded. The observed changes are likely to represent the condition during chronic administration of these drugs in clinical therapy of depression.
测定了一组经不同类型抗抑郁药物慢性（21天）治疗的大鼠中，[3H]丙咪嗪与其在额叶皮质中的识别位点的特异性结合，以及血清素（5-HT）、5-羟吲哚乙酸（5-HIAA）和去甲肾上腺素（NE）的水平，以及粗制突触体（P2）组分对血清素的摄取。这些抗抑郁药物包括：去甲替林、氟西汀、茚满丙二胺、苯乙肼（每天10mg/kg）、马普替林（每天20mg/kg），以及仅给予赋形剂（对照组）。丙咪嗪竞争曲线的定量分析证实存在两类[3H]丙咪嗪位点：对于竞争配体，高亲和力位点的IC50为11.2nM，低亲和力位点的IC50为630nM。高亲和力和低亲和力位点的比例分别为73±4%和26±4%。除茚满丙二胺外，所有抗抑郁药物的慢性治疗均显著降低了丙咪嗪高亲和力位点的亲和力，但未改变其比例。除苯乙肼外，所有治疗均使丙咪嗪在低亲和力位点的IC50更显著增加。氟西汀在改变高亲和力和低亲和力[3H]丙咪嗪识别位点的亲和力方面最为有效。仅苯乙肼治疗可显著提高NE和5-HT水平，而氟西汀治疗后5-HT和5-HIAA水平较低。仅在氟西汀治疗的大鼠中，5-HT摄取动力学发生了显著改变：5-HT摄取速率（Vmax）降低了43%，Km值从104 nM增加到184 nM。未发现丙咪嗪与其结合位点亲和力的变化与受试药物对5-HT水平或摄取的影响相关。它们可能是由于结合蛋白物理化学性质的适应性改变，尽管不能排除残留药物干扰结合测定的存在。观察到的变化可能代表了这些药物在抑郁症临床治疗中慢性给药期间的情况。
