Inhibition of shock-induced foot tapping behaviour in the gerbil by a tachykinin NK1 receptor antagonist
Inhibition of shock-induced foot tapping behaviour in the gerbil by a tachykinin NK1 receptor antagonist
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DOI：
10.1016/s0014-2999(01)00724-5
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发表时间：
2001-02-02
影响因子：
5
通讯作者：
Higgins, GA
中科院分区：
文献类型：
--
作者：
Ballard, TM;Sänger, S;Higgins, GA
选择性速激肽NK 1受体拮抗剂2-（R）-（1-（R）-3，5-双（三氟甲基）苯乙氧基）-3-（S）-（4-氟）苯基-4-（3-氧代-1，2，4-三唑-5-基）甲基吗啉（MK-869）是近年来发现的一种治疗焦虑/抑郁症的新方法。建立速激肽NK 1受体拮抗剂中枢神经系统（CNS）活性的常用模型是抑制NK 1激动剂诱导的沙鼠足敲击。在本研究中，我们表明，脚轻敲也可以诱导在大多数，但不是所有的沙鼠的脚电击和相关的线索。MK-869（0.3-3 mg/kg，i.p.）剂量依赖性地阻断了这种踢踏反应。该效应进一步显示是由于选择性NK 1受体阻断，因为（2S，3S）-顺式-3（2-甲氧基苄基氨基）-2-苯基哌啶（CP-99，994; 3 mg/kg，i. p.）抑制足敲击，而其活性较低的对映体（2 R，3R）-顺式-3-（2-甲氧基苄基氨基）-2-苯基哌啶（CP-100，263; 3 mg/kg，i. p.）没有效果。地西泮（1-10 mg/kg，i. p.）也抑制足敲击，而氟西汀（10-30 mg/kg，i. p.）明显增加了这种行为。目前的数据支持这样的观点，即在沙鼠的脚轻敲是一种行为反应的厌恶刺激，并强烈抑制两个NK 1受体拮抗剂。这些数据支持速激肽NK 1受体拮抗剂作为新型抗焦虑/抗抑郁药的作用。(C)2001 Elsevier Science B. V.保留所有权利。
The selective tachykinin NK1 receptor antagonist, 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine (MK-869), has been recently described as a novel therapeutic approach for anxiety/depression. A frequently used model to establish the central nervous system (CNS) activity of tachykinin NK1 receptor antagonists is the inhibition of NK1 agonist-induced foot tapping in gerbils. In the present study, we demonstrate that foot tapping can also be induced in most, but not all, gerbils by footshock and associated cues. MK-869 (0.3-3 mg/kg, i.p.) dose-dependently blocked this foot tapping response. This effect was further shown to be due to selective NK1 receptor blockade, since (2S,3S)-cis-3(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994; 3 mg/kg, i.p.) inhibited foot tapping, whereas its less active enantiomer (2R,3R)-cis-3(2-methoxybenzylamino)-2-phenylpiperidine (CP-100,263; 3 mg/kg, i.p.) had no effect. Diazepam (1-10 mg/kg, i.p.) also inhibited foot tapping, whereas fluoxetine (10-30 mg/kg, i.p.) markedly increased this behaviour. The present data support the view that foot tapping in the gerbil is a behavioural response to an aversive stimulus, and is robustly inhibited by two NK1 receptor antagonists. The data support a role for tachykinin NK1 receptor antagonists as novel anxiolytic/antidepressants. (C) 2001 Elsevier Science B.V. All rights reserved.