Acute Treatment with the Antidepressant Fluoxetine Internalizes 5-HT1A Autoreceptors and Reduces the In Vivo Binding of the PET Radioligand [18F]MPPF in the Nucleus Raphe Dorsalis of Rat
Acute Treatment with the Antidepressant Fluoxetine Internalizes 5-HT1A Autoreceptors and Reduces the In Vivo Binding of the PET Radioligand [18F]MPPF in the Nucleus Raphe Dorsalis of Rat
复制标题
抗抑郁药氟西汀的急性治疗使 5-HT1A 自身受体内在化，并减少大鼠中缝背核中 PET 放射性配体 [18F]MPPF 的体内结合
DOI：
10.1523/jneurosci.0950-04.2004
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
L. Descarries
中科院分区：
文献类型：
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作者：
M. Riad;L. Zimmer;L. Rbah;K. C. Watkins;M. Hamon;L. Descarries
由于5-HT（serotonin，5-HT）神经元的索马树突上的5-HT 1A受体通常介导5-HT放电和释放的抑制，因此这些自身受体的脱敏对于5-HT再摄取抑制剂（5-HT reuptake inhibitors，SSRIs）处理后获得5-HT传递的增强是必不可少的。我们以前已经证明，使用免疫电子显微镜与特定的5-HT 1A抗体，5-HT 1A自身受体的内化与他们的脱敏在大鼠给予单剂量的5-HT 1A受体激动剂8-羟基-2-（二正丙基氨基）四氢萘。在这里，我们研究了5-HT 1A受体的亚细胞分布在树突中缝背核（NRD）（自体受体）和海马（异源受体）急性治疗后，抗抑郁药SSRI，氟西汀（10毫克/公斤，腹腔注射）。在平行实验中，通过立体定位植入的β微探针测量5-HT 1A正电子发射断层扫描放射性配体4，2-（甲氧基苯基）-1-[2-（N-2-吡啶基）-p-fluorobenzamido]乙基哌嗪（[18 F]MPPF）在这两个脑区域中的体内结合动力学。治疗后1小时，NRD树突质膜的5-HT 1A免疫金标记减少了36%，同时其细胞质标记增加，海马树突无任何变化。[18 F]MPPF的体内结合在NRD中降低了35%，在海马中保持不变。这两种作用均被5-HT 1A受体拮抗剂（N-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]-N-（2-吡啶基）环己烷-甲酰胺）（1 mg/kg，i. p.）预处理阻断。在NRD和海马的脑切片中，[18 F]MPPF放射自显影标记在氟西汀和生理盐水处理的大鼠之间没有差异。这些免疫细胞化学结果证实，5-HT 1A自身受体的内化可能是其脱敏的原因，微探针结果表明，抗抑郁药治疗效果的先决条件可能适用于人类的脑成像。
Because 5-HT1A receptors located on the soma dendrites of serotonin (5-HT) neurons normally mediate an inhibition of 5-HT firing and release, the desensitization of these autoreceptors is essential for obtaining an enhancement of 5-HT transmission after treatment with 5-HT reuptake inhibitors (SSRIs). We have demonstrated previously, using immunoelectron microscopy with specific 5-HT1A antibodies, that an internalization of 5-HT1A autoreceptors is associated with their desensitization in rats given a single dose of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Here, we examined the subcellular distribution of 5-HT1A receptors in dendrites from nucleus raphe dorsalis (NRD) (autoreceptors) and hippocampus (heteroreceptors) after acute treatment with the antidepressant SSRI, fluoxetine (10 mg/kg, i.p.). In parallel experiments, the kinetics of in vivo binding of the 5-HT1A positron emission tomography radioligand 4,2-(methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]ethylpiperazine ([18F]MPPF) was measured in these two brain regions by means of stereotaxically implanted β microprobes. One hour after treatment, there was a 36% decrease in 5-HT1A immunogold labeling of the plasma membrane of NRD dendrites, and a concomitant increase in their cytoplasmic labeling, without any change in hippocampal dendrites. In vivo binding of [18F]MPPF was reduced by 35% in NRD and unchanged in hippocampus. Both effects were blocked by pretreatment with the 5-HT1A receptor antagonist (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide) (1 mg/kg, i.p.). In brain sections of NRD and hippocampus, [18F]MPPF autoradiographic labeling did not differ between fluoxetine- and saline-treated rats. These immunocytochemical results confirmed that internalization of 5-HT1A autoreceptors may account for their desensitization, and the microprobe results suggest that this prerequisite for antidepressant treatment efficacy could be amenable to brain imaging in humans.