Effect of chronic administration of duloxetine on serotonin and norepinephrine transporter binding sites in rat brain
Effect of chronic administration of duloxetine on serotonin and norepinephrine transporter binding sites in rat brain
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DOI：
10.1016/j.biopsych.2006.02.029
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发表时间：
2007-01-15
影响因子：
10.6
通讯作者：
Frazer, Alan
中科院分区：
文献类型：
--
作者：
Gould, Georgianna G.;Javors, Martin A.;Frazer, Alan
背景：长期给予某些选择性5-羟色胺或去甲肾上腺素再摄取抑制剂的大鼠，脑内5-羟色胺和去甲肾上腺素转运体结合部位分别显著减少。度洛西汀可能是一种双重的5-羟色胺/去甲肾上腺素再摄取抑制剂，因为它只是在体外对5-羟色胺的抑制作用略强于去甲肾上腺素。因此，我们假设，慢性度洛西汀治疗，在其治疗范围内，在产生血清水平的剂量下，将以剂量依赖的方式影响两种谷胺转运体，较高的剂量会导致两种转运体的结合位点更大的减少。方法：大鼠每天给予4或8 mg/kg的度洛西汀、帕罗西汀、地塞帕明或皮下微泵给药，为期21天。结果：度洛西汀和帕罗西汀均能显著降低羟色胺转运体与5-羟色胺转运体的结合，但地塞帕明能显著降低去甲肾上腺素转运体与鲁西汀的结合。在达洛西汀的剂量产生的大鼠血清浓度在患者达到的范围内，推荐的每日剂量，度洛西汀在体内更像是一种选择性的5-羟色胺再摄取抑制剂，而不是一种双重再摄取抑制剂，因为它有能力选择性地降低5-羟色胺转运体的密度。
Background: Chronic treatment of rats with certain selective serotonin or norepinepbrine reuptake inhibitors produces significant decreases, respectively, in serotonin and norepinephrine transporter binding sites in brain. Duloxetine may be a dual serotonin/ norepinepbrine reuptake inhibitor, as it is only a slightly more potent inhibitor of serotonin than norepinepbrine uptake in vitro. Consequently, we hypothesized that chronic duloxetine treatment, at doses producing serum levels within its therapeutic range, would affect both morroamine transporters dose-dependently, with a higher dose causing greater reductions of binding sites for both transporters.Methods: Rats were treated with either 4 or 8 mg/kg/d of duloxetine, paroxetine, desipramine, or vehicle via subcutaneous osmotic minipumps for 21 days. Binding sites for serotonin and norepinephrine transporters were measured in amygdala and hippocampus using quantitative autoradiography.Results: Both doses of duloxetine and paroxetine produced equivalent and significant decreases in [H-3] cyanoimipramine binding to serotonin transporters, but only desipramine treatment significantly reduced [HI rusoxetine binding to norepinepbrine transporters.Conclusions. At doses producing rat serum concentrations in the range achieved in patients at recommended daily doses of the drug, duloxetine behaves in vivo more as a selective serotonin reuptake inhibitor than a dual reuptake inhibitor in its capacity to selectively reduce serotonin transporter density.