Role of the NMDA receptor NR2B subunit in the discriminative stimulus effects of ketamine
Role of the NMDA receptor NR2B subunit in the discriminative stimulus effects of ketamine
复制标题
DOI：
10.1097/00008877-200305000-00007
复制
发表时间：
2003-05-01
影响因子：
1.6
通讯作者：
Jentzsch, KR
中科院分区：
文献类型：
--
作者：
De Vry, J;Jentzsch, KR
非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮是一种具有抗痛觉过敏特性的解离性麻醉剂。然而，其临床应用受到拟精神病副作用的影响。由于氯胺酮和其他非竞争性NMDA拮抗剂，如苯环利定和地佐环平，对NMDA受体的NR 2A-2D亚基没有选择性，因此尚不清楚这些亚基中的哪一个是造成拟精神病副作用的原因。本研究调查了NR 2B亚基在氯胺酮药物辨别模型中的作用，这可能与此类副作用相关。在旨在评估一般效力和时间的第一个实验中。依赖性，氯胺酮，地佐环平，苯环利定和NR 2B选择性拮抗剂艾芬地尔和Ro 25-6981，剂量依赖性地抑制大鼠的固定比率10食物强化反应，在15-40分钟左右获得峰值功效。在训练大鼠在两个杠杆固定比率10食物强化程序中区分氯胺酮和载体中，氯胺酮，地佐环平，苯环利定和Ro 25-6981诱导完全泛化（>80%），而艾芬地尔诱导部分泛化（33%）。这些研究结果表明，NR 2B亚基参与非竞争性NMDA拮抗剂的歧视性刺激效应，选择性NR 2B拮抗剂也可能诱导拟精神病的副作用。
The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, is a dissociative anesthetic with antihyperalgesic properties. However, its clinical use is compromised by psychotomimetic side-effects. As ketamine and other noncompetitive NMDA antagonists, such as phencyclidine and dizocilpine, are not selective for the NR2A-2D subunits of the NMDA receptor, it is unclear which of these subunits is responsible for the psychotomimetic side-effects. This study investigated the role of the NR2B subunit in the ketamine drug discrimination model, a possible correlate for such side-effects. In a first experiment aimed at assessing general potency and time. dependency, ketamine, dizocilpine, phencyclidine and the NR2B-selective antagonists ifenprodil and Ro 25-6981, dose-dependently suppressed fixed ratio 10 food-reinforced responding in rats, with peak efficacy obtained around 15-40 min. In rats trained to discriminate ketamine from vehicle in a two-lever fixed ratio 10 food-reinforced procedure, ketamine, dizocilpine, phencyclidine and Ro 25-6981 induced complete generalization (>80%); whereas ifenprodil induced partial generalization (33%). These findings suggest that the NR2B subunit is involved in the discriminative stimulus effects of noncompetitive NMDA antagonists, and that selective NR2B antagonists may also induce psychotomimetic side-effects.