Witkin J M, Tortella F C
Drug Development Group, Psychobiology Laboratory, NIDA Addiction Research Center, Baltimore, MD 21224.
Life Sci. 1991;48(11):PL51-6. doi: 10.1016/0024-3205(91)90516-e.
The anticonvulsants diazepam (1-10 mg/kg) and phenobarbital (30-100 mg/kg) protected against lethality without altering clonic convulsions induced by 75 mg/kg cocaine (CD100) in male Swiss Webster mice. In contrast, the non-competitive N-methyl-D-aspartate (NMDA) antagonists, MK-801 (dizocilpine) and phencyclidine, produced dose-dependent protection against cocaine convulsions. The competitive NMDA antagonists, CPP and NPC 12626, were also anti-convulsant, without producing the behavioral disturbances associated with non-competitive antagonists. Diazepam and phenobarbital protected against convulsions induced by 60 mg/kg cocaine (90% convulsions alone). Compounds that act at the strychnine-insensitive glycine receptor of the NMDA receptor complex, ACPC and 7-chlorokynurinic acid, also protected against convulsions induced by 60 mg/kg cocaine. In contrast, the non-opioid antitussive anticonvulsants (dextromethorphan, caramiphen, and carbetapentane) were not active against either dose of cocaine. The efficacy of compounds as antagonists of the convulsant effects of cocaine and NMDA appear related. These results suggest a potential role for the NMDA receptor complex in the convulsant actions of cocaine and new molecular targets for drug discovery in treating cocaine toxicity.
抗惊厥药地西泮（1 - 10毫克/千克）和苯巴比妥（30 - 100毫克/千克）可保护雄性瑞士韦伯斯特小鼠免受致死性影响，且不改变75毫克/千克可卡因（CD100）诱发的阵挛性惊厥。相比之下，非竞争性N - 甲基 - D - 天冬氨酸（NMDA）拮抗剂MK - 801（地佐环平）和苯环己哌啶可产生剂量依赖性的抗可卡因惊厥作用。竞争性NMDA拮抗剂CPP和NPC 12626也具有抗惊厥作用，且不会产生与非竞争性拮抗剂相关的行为紊乱。地西泮和苯巴比妥可保护小鼠免受60毫克/千克可卡因诱发的惊厥（单独使用时90%会惊厥）。作用于NMDA受体复合物中士的宁不敏感甘氨酸受体的化合物ACPC和7 - 氯犬尿氨酸，也可保护小鼠免受60毫克/千克可卡因诱发的惊厥。相比之下，非阿片类镇咳抗惊厥药（右美沙芬、卡拉美芬和卡比沙明）对两种剂量的可卡因均无活性。这些化合物作为可卡因和NMDA惊厥作用拮抗剂的功效似乎相关。这些结果表明NMDA受体复合物在可卡因惊厥作用中可能发挥作用，并且为治疗可卡因毒性的药物发现提供了新的分子靶点。
