Learning and memory-enhancing effects of Ro 15-4513: a comparison with flumazenil.
Learning and memory-enhancing effects of Ro 15-4513: a comparison with flumazenil.
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Ro 15-4513 的学习和记忆增强作用：与氟马西尼的比较。
DOI：
10.1016/0028-3908(92)90180-w
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发表时间：
1992
影响因子：
4.7
通讯作者：
Lal,H
中科院分区：
文献类型：
--
作者：
Prather,PL;Forster,MJ;Lal,H
合成苯二氮卓类药物会产生顺行性遗忘症，可通过选择性苯二氮卓类拮抗剂或反向激动剂来逆转。因此，有人认为拮抗剂的记忆增强作用是由于内源性“苯二氮卓样”内毒素的拮抗作用。如果苯二氮卓拮抗剂的记忆增强作用主要由此类内源苯二氮卓配体的拮抗作用决定，那么可以假设，施用反向激动剂（其产生与苯二氮卓激动剂功能相反的作用）也可以模仿苯二氮卓拮抗剂的作用，但不会产生比纯拮抗剂更大的作用。因此，本研究的目的是研究苯二氮卓反向激动剂乙基-8-酰胺基-5,6-二氢-5-甲基-6-氧代-4H-咪唑[1,5a][1,4]苯二氮卓-3-羧酸酯(Ro 15-4513)对年轻HSD:(ICR)BR小鼠的记忆增强作用，并将这些作用与对照组小鼠的记忆增强作用进行比较。苯二氮卓类拮抗剂，氟马西尼。预训练注射氟马西尼和 Ro 15-4513（2.5 和 10.0 mg/kg）同样增强了任务的获取和保留 1 周，要求小鼠辨别 T 迷宫的正确臂，以避免轻微电击。 Ro 15-4513 预处理还可以剂量依赖性地保护动物免受由胆碱能受体拮抗剂东莨菪碱在第二种记忆模型中诱导的实验性遗忘症的影响，在该模型中，小鼠在电击后被要求被动地避开暗室。相比之下，在每日主动回避课程之前注射的 Ro 15-4513 未能显着改善获取或保留性能。总的来说，这些结果表明苯二氮卓类反激动剂 Ro 15-4513 具有增强记忆的作用，大约相当于拮抗剂氟马西尼的作用。因此得出的结论是，这些记忆增强作用与这些药物拮抗内源性苯二氮卓类配体的激动作用的能力有关，而不是与它们本身的任何内在活性有关。
Synthetic benzodiazepines produce an anterograde amnesia, which can be reversed by selective benzodiazepine antagonists or inverse agonists. It has therefore been suggested that the memory-enhancing effects of the antagonists are due to antagonism of an endogenous “benzodiazepine-like” endocoid. If the memory-enhancing effects of the benzodiazepine antagonists are determined predominantly by the antagonism of such endogenous benzodiazepine-ligands, then it could be hypothesized that administration of an inverse agonist, which produces effects functionally opposite to those of benzodiazepine agonists, may also mimic the effects of benzodiazepine antagonists but not produce effects greater than those of the pure antagonists. The purpose of the present study was therefore to investigate the memory-enhancing effects of the benzodiazepine inverse agonist, ethyl-8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513) in young HSD:(ICR)BR mice and to compare these effects with those of the benzodiazepine antagonist, flumazenil. Pretraining injections of flumazenil and Ro 15-4513 (2.5 and 10.0 mg/kg) enhanced equally, both the acquisition and the retention of a task for 1 week requiring mice to discriminate the correct arm of a T-maze, to avoid a mild electric shock. Pretreatment with Ro 15-4513 also dose-dependently protected the animals from experimental amnesia, induced by the cholinergic receptor antagonist, scopolamine in a second model of memory, in which mice were required to passively avoid a dark chamber after shock. In contrast, Ro 15-4513, injected prior to daily active avoidance sessions, failed to significantly improve either the acquisition or retention performance. Taken collectively, these results suggest that the benzodiazepine inverse agonist, Ro 15-4513 possessed memory-enhancing effects, approximately equivalent to that of the antagonist, flumazenil. It is therefore concluded that these memory-enhancing effects are related to the ability of these drugs to antagonize the agonistic actions of an endogenous benzodiazepine-like ligand, rather than to any intrinsic activity of their own.