Lee Ho-Joo, Rao Jagadeesh S, Ertley Renee N, Chang Lisa, Rapoport Stanley I, Bazinet Richard P
Brain Physiology and Metabolism Section National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Psychopharmacology (Berl). 2007 Jan;190(1):103-15. doi: 10.1007/s00213-006-0582-1. Epub 2006 Nov 9.
Fluoxetine is used to treat unipolar depression and is thought to act by increasing the concentration of serotonin (5-HT) in the synaptic cleft, leading to increased serotonin signaling. The 5-HT(2A/2C) receptor subtypes are coupled to a phospholipase A(2) (PLA(2)). We hypothesized that chronic fluoxetine would increase the brain activity of PLA(2) and the turnover rate of arachidonic acid (AA) in phospholipids of the unanesthetized rat.
To test this hypothesis, rats were administered fluoxetine (10 mg/kg) or vehicle intraperitoneally daily for 21 days. In the unanesthetized rat, [1-(14)C]AA was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min and its brain was subjected to chemical, radiotracer, or enzyme analysis.
Using equations from our fatty acid model, we found that chronic fluoxetine compared with vehicle increased the turnover rate of AA within several brain phospholipids by 75-86%. The activity and protein levels of brain cytosolic PLA(2) (cPLA(2)) but not of secretory or calcium-independent PLA(2) were increased in rats administered fluoxetine. In a separate group of animals that received chronic fluoxetine followed by a 3-day saline washout, the turnover of AA and activity and protein levels of cPLA(2) were not significantly different from controls. The protein levels of cyclooxygenases 1 and 2 as well as the concentration of prostaglandin E(2) in rats chronically administered fluoxetine did not differ significantly from controls.
The results support the hypothesis that fluoxetine increases the cPLA(2)-mediated turnover of AA within brain phospholipids.
氟西汀用于治疗单相抑郁症，其作用机制被认为是通过增加突触间隙中血清素（5-羟色胺，5-HT）的浓度，从而增强血清素信号传导。5-HT(2A/2C)受体亚型与磷脂酶A(2)（PLA(2)）偶联。我们推测，长期使用氟西汀会增加未麻醉大鼠大脑中PLA(2)的活性以及磷脂中花生四烯酸（AA）的周转率。
为验证这一推测，大鼠每天腹腔注射氟西汀（10毫克/千克）或赋形剂，持续21天。在未麻醉的大鼠中，静脉注射[1-(14)C]AA，并采集动脉血浆样本，直至5分钟后处死动物，随后对其大脑进行化学、放射性示踪或酶分析。
利用我们脂肪酸模型中的公式，我们发现，与赋形剂相比，长期使用氟西汀可使几种脑磷脂中AA的周转率提高75 - 86%。在接受氟西汀治疗的大鼠中，脑细胞质PLA(2)（cPLA(2)）的活性和蛋白质水平升高，但分泌型或非钙依赖性PLA(2)的活性和蛋白质水平未升高。在另一组接受长期氟西汀治疗后用生理盐水冲洗3天的动物中，AA的周转率以及cPLA(2)的活性和蛋白质水平与对照组无显著差异。长期服用氟西汀的大鼠中，环氧化酶1和2的蛋白质水平以及前列腺素E(2)的浓度与对照组无显著差异。
这些结果支持了氟西汀增加大脑磷脂中cPLA(2)介导的AA周转率这一推测。
