Qu Ying, Chang Lisa, Klaff Justin, Seemann Ruth, Rapoport Stanley I
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Neuropsychopharmacology. 2003 Jul;28(7):1219-26. doi: 10.1038/sj.npp.1300177. Epub 2003 May 7.
Fluoxetine, a selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, is used widely to treat depression and related disorders. By inhibiting presynaptic 5-HT reuptake, fluoxetine is thought to act by increasing 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT(2A/2C) receptors. These receptors can be coupled via a G-protein to phospholipase A(2) (PLA(2)), which when activated releases the second messenger arachidonic acid from synaptic membrane phospholipids. To image this activation, fluoxetine (10 mg/kg) or saline vehicle was administered i.p. to unanesthetized rats, and regional brain incorporation coefficients k() of intravenously injected radiolabeled arachidonic acid were measured after 30 min. Compared with vehicle, fluoxetine significantly increased k() in prefrontal, motor, somatosensory, and olfactory cortex, as well as in the basal ganglia, hippocampus, and thalamus. Many of these regions demonstrate high densities of the serotonin reuptake transporter and of 5-HT(2A/2C) receptors. Brain stem, spinal cord, and cerebellum, which showed no significant response to fluoxetine, have low densities of the transporters and receptors. The results show that it is possible to image quantitatively PLA(2)-mediated signal transduction in vivo in response to fluoxetine.
氟西汀是一种选择性5-羟色胺（5-ht）再摄取抑制剂，广泛用于治疗抑郁症和相关疾病。通过抑制突触前5-ht再摄取，氟西汀被认为是通过增加突触间隙中的5-ht起作用，从而使5-ht与突触后5-ht（2A/2C）受体结合。这些受体可通过G蛋白与磷脂酶A（2）（PLA（2））偶联，激活后从突触膜磷脂中释放第二信使花生四烯酸。为了成像这种激活，将氟西汀（10mg/kg）或生理盐水载体腹腔注射给未麻醉的大鼠，并在30分钟后测量静脉注射放射性标记花生四烯酸的脑区摄取系数k（）。与载体相比，氟西汀显著增加了前额叶、运动、体感和嗅觉皮层以及基底神经节、海马体和丘脑的k（）。这些区域中的许多都显示出5-羟色胺再摄取转运体和5-ht（2A/2C）受体的高密度。对氟西汀无明显反应的脑干、脊髓和小脑，其转运体和受体密度较低。结果表明，有可能在体内对氟西汀反应的PLA（2）介导的信号转导进行定量成像。
