In vivo labeling of serotonin uptake sites with [3H]paroxetine.
In vivo labeling of serotonin uptake sites with [3H]paroxetine.
复制标题
用[3H]帕罗西汀体内标记血清素摄取位点。
DOI：
10.1111/j.1471-4159.1989.tb09215.x
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发表时间：
1989
影响因子：
4.7
通讯作者：
Hartig,PR
中科院分区：
文献类型：
--
作者：
Scheffel,U;Hartig,PR
以前的工作表明，[~3H]帕罗西汀是哺乳动物大脑中5-羟色胺摄取部位的一种有效和选择性的体外标记。在本研究中，[~3H]帕罗西汀作为5-羟色胺摄取部位的活体标记在小鼠身上进行了测试。大鼠尾静脉注射氚后1h，全脑氚浓度达最大值(静脉剂量的1.4%)。示踪剂在注射后3h的分布与先前的体外结合研究中已知的5-羟色胺摄取部位的分布一致(r=0.85)。帕罗西汀浓度最高的脑区依次为：下丘脑和GT、额叶皮质和GT、嗅结节和GT、丘脑和GT、上丘和脑干、海马体和纹状体、小脑。预先注射载体帕罗西汀(1 mg/kg)可显著降低除小脑以外所有区域的[~3H]帕罗西汀浓度，小脑是已知的含有相对较少的特定结合位点的区域。动力学研究显示，在注射后2小时，帕罗西汀的特异性结合(组织减去小脑)最高，此后活性清除缓慢(从下丘脑解离的一半时间，215分钟)。通过在给药前5min预先注射单胺摄取阻断剂或受体拮抗剂来研究体内[~3H]帕罗西汀结合的特异性。5-羟色胺或毒扁豆碱能胆碱能受体拮抗剂和多巴胺或去甲肾上腺素摄取阻滞剂不会减少[~3H]帕罗西汀的体内结合。相反，本研究中5-羟色胺摄取阻滞剂的体内抑制效力与先前发表的脑突触体5-羟色胺摄取抑制的体外数据之间有很好的相关性(r=0.99)。此外，下丘脑与[~3H]帕罗西汀的结合被发现受到立体特异性的抑制，(Z)-去甲咪胺的效力比同分异构体高四倍以上。这些研究表明，[~3H]帕罗西汀是一种有效的、选择性的脑5-羟色胺摄取部位的体内标记药物。
Previous work has shown that [3H]paroxetine is a potent and selective in vitro label for serotonin uptake sites in the mammalian brain. In the present study, [3H]paroxetine was tested in mice as an in vivo label for serotonin uptake sites. Maximum tritium concentration in the whole brain (1.4% of the intravenous dose) was reached 1 h after injection into a tail vein. Distribution of the tracer at 3 h after injection followed the distribution of serotonin uptake sites known from previous in vitro binding studies (r= 0.85). The areas of highest [3H]paroxetine concentration, in decreasing order, were: hypothalamus > frontal cortex > olfactory tubercles > thalamus > upper colliculi > brainstem > hippocampus > striatum > cerebellum. Preinjection of carrier paroxetine (1 mg/kg) significantly decreased [3H]paroxetine concentration in all areas except in the cerebellum, which is known to contain a relatively low number of specific binding sites. Kinetic studies showed highest specific [3H]paroxetine binding (tissue minus cerebellum) at 2 h after injection and slow clearance of activity thereafter (half‐time of dissociation from the hypothalamus, 215 min). The specificity of in vivo [3H]paroxetine binding was studied by preinjecting monoamine uptake blockers or receptor antagonists 5 min before administration of [3H]paroxetine. Serotonergic or muscarinic cholinergic receptor antagonists and dopamine or norepinephrine uptake blockers did not reduce the in vivo binding of [3H]paroxetine. In contrast, there was an excellent correlation (r= 0.99) between the in vivo inhibitory potencies of serotonin uptake blockers in this study and previously published in vitro data on inhibition of [3H]serotonin uptake in brain synaptosomes. In addition, [3H]paroxetine binding in the hypothalamus was found to be stereospecifically inhibited, (Z)‐norzimelidine displaying a greater than fourfold higher potency than theEisomer. These studies indicate that [3H]paroxetine is a potent and selective agent for the in vivo labeling of cerebral serotonin uptake sites.