Geter-Douglass B, Witkin J M
Drug Development Group, NIDA Addiction Research Center, National Institutes of Health, Baltimore, MD 21224, USA.
Psychopharmacology (Berl). 1997 Sep;133(1):43-50. doi: 10.1007/s002130050369.
Several non-competitive NMDA receptor ion channel blockers, competitive NMDA antagonists and compounds acting at other sites on the NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of dizocilpine. Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor antagonist, dizocilpine (0.17 mg/kg), from saline in a T-maze. Mice rapidly acquired the discrimination with minimal amounts of drugs required for training and testing. Several non-competitive antagonists dose-dependently substituted for dizocilpine with a rank order of potency of dizocilpine > TCP > (-)-MK-801 > SKF 10,047 > dextrorphan > PCP. There was a positive correlation between the potencies of the compounds that substituted for dizocilpine and their previously reported affinities for the [3H]dizocilpine binding site of the NMDA receptor ion channel. Compounds acting at other sites on the NMDA receptor complex, including NMDA, the partial agonist at the strychnine-insensitive glycine site, ACPC, and the polyamine antagonist, ifenprodil, failed to substitute fully. In addition, the AMPA antagonist, NBQX, the monoamine uptake inhibitor, cocaine, and the GABAA receptor agonists, diazepam and phenobarbital, failed to substitute fully for dizocilpine. However, like the ion channel blockers, the competitive NMDA antagonists, CGS 19755, NPC 17742, (+/-)CPP and LY 233536 dose-dependently substituted for dizocilpine. The competitive antagonist, LY 274614, and its active enantiomer, LY 235959, failed to substitute for dizocilpine, each producing severe disruptions in locomotor activity. That most of the competitive antagonists substituted for dizocilpine is in accordance with other behavioral data (e.g., ataxia, locomotor activity) documenting similarities in the effects of non-competitive and competitive antagonists. These findings are also consistent with results of clinical investigations suggesting overlap in the behavioral and subjective profiles of competitive and non-competitive NMDA blockers.
研究了几种非竞争性N-甲基-D-天冬氨酸（NMDA）受体离子通道阻滞剂、竞争性NMDA拮抗剂以及作用于NMDA受体复合物其他位点的化合物，以考察它们替代地佐环平辨别刺激效应的能力。用食物训练瑞士韦伯斯特小鼠在T型迷宫中区分非竞争性NMDA受体拮抗剂地佐环平（0.17毫克/千克）和生理盐水。小鼠用极少量用于训练和测试的药物就能迅速学会这种辨别。几种非竞争性拮抗剂呈剂量依赖性地替代地佐环平，其效价顺序为地佐环平＞TCP＞（-）-MK-801＞SKF 10,047＞右啡烷＞苯环己哌啶。替代地佐环平的化合物效价与其先前报道的对NMDA受体离子通道[3H]地佐环平结合位点的亲和力之间存在正相关。作用于NMDA受体复合物其他位点的化合物，包括NMDA、士的宁不敏感甘氨酸位点的部分激动剂ACPC以及多胺拮抗剂ifenprodil，均不能完全替代。此外，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）拮抗剂NBQX、单胺摄取抑制剂可卡因以及γ-氨基丁酸A（GABAA）受体激动剂地西泮和苯巴比妥也不能完全替代地佐环平。然而，与离子通道阻滞剂一样，竞争性NMDA拮抗剂CGS 19755、NPC 17742、（±）-CPP和LY 233536呈剂量依赖性地替代地佐环平。竞争性拮抗剂LY 274614及其活性对映体LY 235959不能替代地佐环平，二者均对运动活动产生严重干扰。大多数竞争性拮抗剂能替代地佐环平，这与其他行为学数据（如共济失调、运动活动）一致，这些数据证明了非竞争性和竞争性拮抗剂效应的相似性。这些发现也与临床研究结果一致，表明竞争性和非竞争性NMDA阻滞剂在行为和主观特征上存在重叠。
