Blockade of chronic tolerance to ethanol by the NMDA antagonist, (+)-MK-801.
Blockade of chronic tolerance to ethanol by the NMDA antagonist, (+)-MK-801.
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DOI：
10.1016/0014-2999(93)90444-m
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发表时间：
1993-02
影响因子：
5
通讯作者：
P. Wu;S. Mihic;J. F. Liu;A. Lê;H. Kalant
中科院分区：
文献类型：
--
作者：
P. Wu;S. Mihic;J. F. Liu;A. Lê;H. Kalant
以往的研究表明，学习和记忆在乙醇耐受性的发展中起着重要作用。（+）-MK-801已被证明会损害学习能力，因此也可能阻碍对乙醇的耐受性的发展。为了验证这种可能性，我们对大鼠进行了一项复杂的运动协调测试——运动带的判断训练。急性静脉注射(+)-MK-801（一种非竞争性NMDA通道阻滞剂）在该试验中产生剂量相关损伤。0.1 mg/kg的剂量本身的作用可以忽略不计，却增强了乙醇的急性效应。在不同动物的慢性实验中，一半的大鼠每天接受(+)-MK-801或生理盐水，30分钟后给予乙醇（1.8 g/kg / p）和三次带上练习，1小时后给予第二剂量(+)-MK-801或生理盐水。另外一半人服用同样的药物，但酒精遵循同样的做法。（+）-MK-801在乙醇前剂量为0.25 mg/kg时阻断了两组小鼠对乙醇的功能耐受，而在乙醇前剂量为0.1 mg/kg时则无阻滞作用。对(+)-MK-801本身的耐受性在治疗2周后未发生。这些结果表明，NMDA受体参与了对乙醇的慢性耐受性的发展，正如之前所示的快速耐受性。
Previous studies indicated that learning and memory play important roles in the development of tolerance to ethanol. (+)-MK-801 has been shown to impair learning and might thus also block the development of tolerance to ethanol. To test this possibility, rats were trained to criterion on the moving belt, a complex motor coordination test. Acute i.p. injection of (+)-MK-801 (a non-competitive NMDA channel blocker) produced dose-related impairment on this test. A dose of 0.1 mg/kg, that had negligible effect by itself, potentiated the acute effects of ethanol. In a chronic experiment with different animals, half of the rats received (+)-MK-801 or saline daily, followed 30 min later by ethanol (1.8 g/kg i.p.) and three practice runs on the belt, and 1 h later a second dose of (+)-MK-801 or saline. The other half received the same drugs but ethanolfollowedthe practice. (+)-MK-801 blocked the functional tolerance to ethanol in both groups when the pre-ethanol dose was 0.25 mg/kg, but not when it was 0.1 mg/kg. Tolerance to the effects of (+)-MK-801 itself did not occur over 2 weeks of treatment. these results suggest that NMDA receptors are involved in development of chronic tolerance to ethanol as shown previously with rapid tolerance.