Löscher W, Annies R, Hönack D
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Eur J Pharmacol. 1993 Oct 5;242(3):263-74. doi: 10.1016/0014-2999(93)90250-l.
The uncompetitive NMDA receptor antagonist, MK-801 (dizocilpine) and the competitive NMDA receptor antagonists, CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid) and its ethyl ester CGP 39551, were compared with respect to behavioural and neurochemical effects in handling-habituated rats. Dopamine, serotonin and their precursors and metabolites were determined in 14 brain regions. Furthermore, adrenaline and noradrenaline were analysed in regional brain tissue. When MK-801 and CGP 37849 were administered at doses which induced similar amphetamine-like behavioural effects (hyperlocomotion, stereotypies), both drugs produced comparable increases in dopamine and serotonin metabolism in various brain regions, thus strongly indicating that these neurochemical alterations were mediated by NMDA receptors. The most marked increases in dopamine turnover were found in mesolimbic areas such as the nucleus accumbens, whereas the most pronounced increases in serotonin metabolism were found in (dorsal) striatum and different parts of the cerebral cortex. In contrast, CGP 39551 differed from MK-801 and CGP 37849 both behaviourally and neurochemically in that amphetamine-like behavioural adverse effects were much less intense and dopamine and serotonin metabolism was not altered in most brain regions. In addition to effects on dopaminergic and serotonergic systems, all three drugs induced changes in adrenaline and/or noradrenaline levels in some brain regions. The data demonstrate that competitive NMDA receptor antagonists, such as CGP 37849, produce activation of dopaminergic and serotonergic pathways similar to that caused by uncompetitive NMDA receptor antagonists, provided that behaviourally equipotent doses are administered.
在习惯处理的大鼠中，比较了非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801（地佐环平）和竞争性NMDA受体拮抗剂CGP 37849（DL-(E)-2-氨基-4-甲基-5-膦酰基-3-戊烯酸）及其乙酯CGP 39551在行为和神经化学方面的作用。测定了14个脑区中的多巴胺、5-羟色胺及其前体和代谢产物。此外，还分析了脑区组织中的肾上腺素和去甲肾上腺素。当以诱导相似的苯丙胺样行为效应（运动亢进、刻板行为）的剂量给予MK-801和CGP 37849时，两种药物在各个脑区均使多巴胺和5-羟色胺代谢产生相当程度的增加，因此有力地表明这些神经化学改变是由NMDA受体介导的。多巴胺周转率的最显著增加见于中脑边缘区域，如伏隔核，而5-羟色胺代谢的最显著增加见于（背侧）纹状体和大脑皮层的不同部位。相比之下，CGP 39551在行为和神经化学方面与MK-801和CGP 37849不同，在于其苯丙胺样行为不良反应强度要小得多，且在大多数脑区中多巴胺和5-羟色胺代谢未发生改变。除了对多巴胺能和5-羟色胺能系统产生作用外，这三种药物均在某些脑区引起肾上腺素和/或去甲肾上腺素水平的变化。数据表明，只要给予行为等效剂量，竞争性NMDA受体拮抗剂，如CGP 37849，会产生与非竞争性NMDA受体拮抗剂所引起的类似的多巴胺能和5-羟色胺能途径激活。
