Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents:: Effects of GYKI 52466 and its novel analogues
Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents:: Effects of GYKI 52466 and its novel analogues
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DOI：
10.1007/s00213-008-1121-z
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发表时间：
2008-06-01
影响因子：
3.4
通讯作者：
Levay, Gyoergy
中科院分区：
文献类型：
--
作者：
Kapus, Gabor L.;Gacsalyi, Istvan;Levay, Gyoergy
目的评价2，3-苯二氮卓类(2，3-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic diazepine，2，3BDZ)型AMPA受体拮抗剂在不同焦虑模型中的抗焦虑作用。材料与方法全细胞电流、海马场电位、加高迷宫、间氯苯基哌嗪(MCPP)诱导的焦虑模型，结果参比化合物GYKI 52466在两种非镇静剂量的焦虑模型中均表现出较强的抗焦虑活性：EPM(0.01 mg/kg)GYKI 53405和GYKI 53655具有抗焦虑活性。EGIS-8332在EPM和LD中具有活性，而EGIS-9637在EPM、mCPP和Vogel模型中具有抗焦虑活性。在EPM和Vogel模型测试的2，3BDZ中，EGIS-10608是最有效的化合物(Med分别为0.01mgkg和2.5mgkg)。在焦虑模型中，2，3BDZ的活性剂量低于镇静作用的剂量。NBQX仅在EPM(3 mg/kg)具有抗焦虑活性。结论非竞争性AMPA受体拮抗剂可独立于其运动抑制活性而显著阻断啮齿动物的焦虑样行为。然而，较高剂量的镇静作用可能会限制其作为新的抗焦虑药物的治疗作用。
Rationale Although emerging number of data supports the role of glutamate receptors and the potential of their antagonists in anxiety disorders, the involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in anxiety is less well characterized.Objective To evaluate the anxiolytic potential of 2,3-benzodiazepine (2,3BDZ) type AMPA receptor antagonists in various models of anxiety.Materials and methods Whole-cell currents, hippocampal field potentials, elevated plus maze (EPM), meta-chlorophenylpiperazine (mCPP)-induced anxiety model, Vogel test in rats and light-dark test (LD) in mice were used to determine AMPA/kainite receptor properties and anxiolytic-like activity of a series of 2,3BDZ-type compounds.Results The reference compound GYKI 52466 was proved active in two anxiety models in non-sedative doses: minimal effective dose (MED) was especially low in EPM (0.01 mg/kg) GYKI 53405 and GYKI 53655 showed anxiolytic-like activity in two tests (EPM and mCPP). EGIS-8332 was active in EPM and LD while EGIS-9637 showed anxiolytic-like potency in EPM, mCPP and Vogel model. EGIS-10608 was the most effective compound among 2,3BDZs tested in EPM and Vogel models (MEDs are 0.01 and 2.5 mg/kg, respectively). 2,3BDZs were active in anxiety models at doses lower than those produced sedative effects. NBQX showed anxiolytic-like activity in EPM only (3 mg/kg).Conclusions The results show that non-competitive AMPA receptor antagonists can profoundly block anxiety-like behavior in rodents independently from their motor depressant activity. However, the sedative properties at higher doses might limit their therapeutic utility as new anxiolytic drugs.