THE EFFECTS OF SINGLE AND REPEATED ANORECTIC DOSES OF 5-HYDROXYTRYPTAMINE UPTAKE INHIBITORS ON INDOLE LEVELS IN RAT-BRAIN
THE EFFECTS OF SINGLE AND REPEATED ANORECTIC DOSES OF 5-HYDROXYTRYPTAMINE UPTAKE INHIBITORS ON INDOLE LEVELS IN RAT-BRAIN
复制标题
DOI：
10.1111/j.1476-5381.1993.tb13817.x
复制
发表时间：
1993-09-01
影响因子：
7.3
通讯作者：
GARATTINI, S
中科院分区：
文献类型：
--
作者：
CACCIA, S;ANELLI, M;GARATTINI, S
1比较了近期上市的5-羟色胺（5-HT）摄取抑制剂的急性和重复等效厌食剂量（ED 50）对大鼠脑吲哚含量的影响，并与原型药物及其已知活性代谢物的脑区域浓度相关。氟西汀（35 μ mol kg-1）、氟伏沙明（60 μ mol kg-1）、帕罗西汀（20 μ mol kg-1）和舍曲林（49 μ mol kg-1）的厌食ED 50的剂量轻微降低脑5-羟基吲哚乙酸（5-HIAA），具有区域差异，这与5-HT摄取阻断一致。只有氟伏沙明和舍曲林显著增加了皮质中5-HT的含量。3对给定药物的急性效应的区域敏感性与任何优先药物分布无关，因为这些化合物几乎均匀地分布在所考虑的脑区域中（皮层、纹状体和海马）。4每天两次重复相同剂量，腹膜内注射，持续14天，然而，得到了不同的图片，在最后一次给药后1小时，与成对喂养的对照动物相比，氟伏沙明对吲哚和氟西汀的含量几乎没有或没有影响，帕罗西汀和舍曲林降低了所有脑区域中的5-HT和5-HIAA。5一周后，只有氟西汀治疗的动物仍然具有降低的脑5-HT，这可能与长期给药后其主要代谢物去甲氟西汀在大鼠脑中的蓄积有关。6需要进一步研究长期神经化学变化与厌食活性之间的关系，但从这些结果来看，对5-羟色胺具有类似急性效应的厌食药物可能与对5-羟色胺具有类似急性效应的药物相似。HT摄取可能在其对5-HT机制的长期影响方面有所不同。
1 The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5-hydroxytryptamine (5-HT) uptake inhibitors on the content of brain indoles were compared in rats in relation to the brain regional concentrations of unchanged drug and its known active metabolite.2 Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 mumol kg-1), fluvoxamine (60 mumol kg-1), paroxetine (20 mumol kg-1) and sertraline (49 mumol kg-1) slightly reduced brain 5-hydroxyindoleacetic acid (5-HIAA), with regional differences, this being compatible with 5-HT uptake blockade. Only fluvoxamine and sertraline significantly enhanced the content of 5-HT in the cortex.3 The regional sensitivity to the acute effect of a given drug was not related to any preferential drug distribution, as these compounds distributed almost uniformly in the brain areas considered (cortex, striatum and hippocampus).4 Repeating the same doses twice daily, i.p. for 14 days, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertraline lowering both 5-HT and 5-HIAA in all the brain regions compared to pair-fed control animals, 1 h after the last dose.5 One week later only fluoxetine-treated animals still had reduced brain 5-HT, this probably being related to the accumulation of its main metabolite norfluoxetine in rat brain after chronic dosing.6 Further studies on the relationship between the long-term neurochemical changes and anorectic activity are required but it appears from these results that anorectic drugs with similar acute effects on 5-HT uptake may differ in their long-term effects on 5-HT mechanisms.