NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations.
NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations.
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DOI：
10.1016/0014-2999(91)90141-c
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发表时间：
1991-02
影响因子：
5
通讯作者：
J. Kehne;T. Mccloskey;B. M. Baron;E. M. Chi;B. Harrison;J. Whitten;M. Palfreyman
中科院分区：
文献类型：
--
作者：
J. Kehne;T. Mccloskey;B. M. Baron;E. M. Chi;B. Harrison;J. Whitten;M. Palfreyman
断奶前的幼鼠从窝中取出时会发出超声波。这些“分离诱导的发声”（SIV）被经典的苯二氮卓类抗焦虑药和缺乏肌肉松弛和镇静特性的非苯二氮卓类抗焦虑药抑制。本研究使用SIV模型来评估靶向与NMDA受体复合物相关的不同位点的化合物的潜在抗焦虑特性。与影响苯二氮卓类或5-羟色胺（5-HT）受体的药物进行了比较。使用“TIP”（斜面上的时间）评估肌肉松弛潜力，即幼犬能够在陡峭斜面上保持其位置的时间量。中枢作用的肌肉松弛剂美芬甘油醚显著抑制TIP，但不抑制SIV。苯二氮卓类激动剂地西泮抑制SIV和TIP，而5-HT 1A部分激动剂丁螺环酮和MDL 73，005 EF抑制SIV而不影响TIP。5-HT 2拮抗剂MDL 11，939抑制TIP，但不抑制SIV，而5-HT 3拮抗剂MDL 73，147 EF对上述两项指标均无影响。SIV被NMDA拮抗剂抑制，包括作用于谷氨酸识别位点的拮抗剂（D，L-氨基-膦酰基戊酸（AP 5）和MDL 100，453）或作用于离子通道的拮抗剂（MK-801），或被士的宁不敏感的甘氨酸拮抗剂5，7-二氯犬尿烯酸（5，7-DCKA）抑制。AP 5、MDL 100，453和MK-801对TIP的抑制作用更强，而5，7-DCKA对此无活性。因此，作用于谷氨酸识别位点上不同位点的拮抗剂表现出潜在的抗焦虑活性，但甘氨酸拮抗剂在其缺乏显著的肌肉松弛副作用方面是不寻常的。
Pre-weaning rat pups emit ultrasonic vocalizations when removed from the litter. These ‘separation-induced vocalizations’ (SIV) are suppressed by classical benzodiazepine anxiolytics and by non-benzodiazepine anxiolytics which lack muscle relaxant and sedative propertes. The present study used the SIV model to assess potential anxiolytic properties of compounds which target different sites associated with the NMDA receptor complex. Comparison was made to drugs which affect benzodiazepine or serotonin (5-HT) receptors. Muscle relaxant potential was assessed using ‘TIP’ (time on an inclined plane), the amount of time a pup was able to retain its position on a steeply inclined surface. Mephenesin, a centrally acting muscle relaxant, significantly suppressed TIP but not SIV. The benzodiazepine agonist diazepam suppressed both SIV and TIP, whereas the 5-HT1Apartial agonists, buspirone and MDL 73,005EF, suppressed SIV without affecting TIP. The 5-HT2antagonist MDL 11,939 suppressed TIP but not SIV, whereas neither measure was affected by the 5-HT3antagonist MDL 73,147EF. SIV was suppressed by NMDA a antagonist including those acting at the glutamate recognition site (D,L-amino-phosphonovaleric acid (AP5) and MDL 100,453) or at the ion channel (MK-801), or by the strychnine-insensitive glycine antagonist 5,7-dichlorokynurenic acid (5,7-DCKA). TIP was suppressed even more potently by AP5, MDL 100,453 and MK-801, whereas 5,7-DCKA was inactive on this measure. Thus, antagonists acting at different sites present on the glutamate recognition site exhibit potential anxiolytic activity, but the glycine antagonist was unusual in its lack of prominent muscle relaxant side effects.