期刊
EUROPEAN NEUROPSYCHOPHARMACOLOGY
卷 25, 期 4, 页码 544-556出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.euroneuro.2015.01.005
关键词
Antidepressants; Yuanzhi-1; Triple reuptake inhibitors; Animal models
资金
- National Natural Science Foundation of China [81001653]
- Beijing Natural Science Foundation [7152019]
- National Key New Drug Creation Programme [2012ZX09102101-004]
Triple reuptake inhibitors that block dopamine transporters (DATs), norepinephrine transporters (NETs), and serotonin transporters (SERTs) are being developed as a new class of antidepressants that might have better efficacy and fewer side effects than traditional antidepressants. In this study, we performed in vitro binding and uptake assays as well as in vivo behavioural tests to assess the pharmacological properties and antidepressant-like efficacy of Yuanzhi-1. In vitro, Yuanzhi-1 had a high affinity for SERTs, NETs, and DATs prepared from rat brain tissue (K-i=3.95, 4.52 and 0.87 nM, respectively) and recombinant cells (K-i=2.87, 6.86 and 1.03 nM, respectively). Moreover, Yuanzhi-1 potently inhibited the uptake of serotonin (5-hydroxytryptamine; 5-HT), norepinephrine (NE) and dopamine (DA) into rat brain synaptosomes (K-i=2.12, 4.85 and 1.08 nM, respectively) and recombinant cells (K-i=1.65, 5.32 and 0.68 nM, respectively). In vivo, Yuanzhi-1 decreased immobility in a dose-dependent manner, which was shown among rats via the forced-swim test (FST) and mice via the tail-suspension test (TST). The results observed in the behavioural tests did not appear to result from the stimulation of locomotor activity. Repeated Yuanzhi-1 treatment (2.5, 5 or 10 mg/kg) significantly reversed depression-like behaviours in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis studies showed that 5- and 10-mg/kg administrations of Yuanzhi-1 significantly increased the extracellular concentrations of 5-HT, NE and DA in the frontal cortices of freely moving rats. Therefore, Yuanzhi-1 might represent a novel triple reuptake inhibitor and possess antidepressant-like activity. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据