Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice.
Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice.
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DOI：
10.1016/j.plefa.2014.01.003
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Basselin M
中科院分区：
文献类型：
--
作者：
Ramadan E;Blanchard H;Cheon Y;Fox MA;Chang L;Chen M;Ma K;Rapoport SI;Basselin M
据报道，胎儿和围产期暴露于选择性5-羟色胺（5-HT）再摄取抑制剂（SSRIs）可改变儿童期行为，而啮齿动物短暂的早期暴露可改变其行为，并减少成年期脑细胞外5-HT。由于5-HT 2A/2C受体介导的神经传递可能涉及G蛋白偶联激活胞质磷脂酶A2（cPLA 2），从突触膜磷脂中释放花生四烯酸（ARA），因此我们假设出生后短暂暴露于氟西汀会降低成年小鼠的脑ARA代谢。在每天注射氟西汀（10 mg/kg i. p.）的未麻醉成年小鼠静脉内输注[1- 14 C]ARA后，对脑ARA掺入系数k* 和速率Jin进行定量成像。或生理盐水。脑ARA代谢酶和其他相关标志物的表达也被测量。在神经影像学上，与盐水处理的成年小鼠相比，早期氟西汀中的k* 和Jin广泛降低。在测量的酶中，cPLA 2活性不变，而Ca 2+非依赖性iPLA 2活性增加。细胞色素P450（CYP 450）4A蛋白水平显著降低74%，该蛋白可将ARA转化为20-HETE。在出生后短暂暴露于氟西汀的成年小鼠中，脑ARA代谢降低，CYP 4A蛋白降低74%，表明脑ARA代谢和CYP 4A代谢产物中的长期效应与药物存在无关。人类的类似变化可能有助于报告早期SSRI后行为的改变。
Fetal and perinatal exposure to selective serotonin (5-HT) reuptake inhibitors (SSRIs) has been reported to alter childhood behavior, while transient early exposure in rodents is reported to alter their behavior and decrease brain extracellular 5-HT in adulthood. Since 5-HT2A/2C receptor-mediated neurotransmission can involve G-protein coupled activation of cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (ARA) from synaptic membrane phospholipid, we hypothesized that transient postnatal exposure to fluoxetine would decrease brain ARA metabolism in adult mice. Brain ARA incorporation coefficients k* and rates Jin were quantitatively imaged following intravenous [1-14C]ARA infusion of unanesthetized adult mice that had been injected daily with fluoxetine (10 mg/kg i.p.) or saline during postnatal days P4–P21. Expression of brain ARA metabolic enzymes and other relevant markers also was measured. On neuroimaging, k* and Jin was decreased widely in early fluoxetine- compared to saline-treated adult mice. Of the enzymes measured, cPLA2 activity was unchanged, while Ca2+-independent iPLA2 activity was increased. There was a significant 74% reduced protein level of cytochrome P450 (CYP) 4A, which can convert ARA to 20-HETE. Reduced brain ARA metabolism in adult mice transiently exposed to postnatal fluoxetine, and a 74% reduction in CYP4A protein, suggest long-term effects independent of drug presence in brain ARA metabolism, and in CYP4A metabolites. Comparable changes in humans might contribute to reported altered behavior following early SSRI.
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影响因子：
4.2
作者：
DEGEORGE, JJ;NORONHA, JG;RAPOPORT, SI
通讯作者：
RAPOPORT, SI
影响因子：
--
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通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
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影响因子：
8.3
作者：
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通讯作者：
Roman, RJ
影响因子：
15.9
作者：
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通讯作者：
Soberman, R