Sharkey J, Ritchie I M, Butcher S P, Kelly J S
Fujisawa Institute of Neuroscience in Edinburgh, Department of Pharmacology, University of Edinburgh, UK.
Brain Res. 1996 Sep 30;735(1):67-82. doi: 10.1016/0006-8993(96)00574-4.
Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can be readily distinguished by their effects on local cerebral glucose utilisation (1CGU). In the present study we compare the effects of the novel NMDA antagonist, (+)-1-methyl-1phenyl-1,2,3,4-tetrahydroisoquinoline (FR115427) on 1CGU, comparing its metabolic profile with that of the non-competitive NMDA receptor antagonist, dizocilpine (MK801) and of the competitive NMDA receptor antagonist CGS19755, using the 2-deoxyglucose metabolic mapping approach. Local cerebral glucose utilisation was measured in 80 anatomically discrete regions of the conscious rat brain using [14C]2-deoxyglucose quantitative autoradiography. Studies were initiated 10 min after the administration of FR115427 (0.1-3 mg/kg i.v.; n = 20), dizocilpine (0.03-0.3 mg/kg; n = 15), CGS19755 (1-30 mg/kg; n = 15) or saline (2 ml/kg; n = 5). Dizocilpine produced characteristic alterations in 1CGU with widespread increases in 1CGU in primary olfactory and limbic areas while reducing 1CGU in somatosensory and motor cortex. FR115427 produced a pattern of altered 1CGU which was broadly similar to that elicited by dizocilpine with increases in 1CGU in the pontine nuclei, presubiculum and hippocampus and reductions in somatosensory and motor cortex and within components of the auditory system. However, FR115427 was approximately 30-fold less potent than dizocilpine in this regard. In limbic structures, the effects of FR115427 were less pronounced than those produced by dizocilpine. Increases in 1CGU of 62-98% were found in retrosplenial, piriform and entorhinal cortex of dizocilpine-treated rats whereas these areas appeared relatively unaffected following FR115427 administration. A comparison of the pattern of metabolic response produced by each of these agents was performed by constructing a hierarchy of regional responsiveness using the f statistic: while focal differences in the metabolic profiles of dizocilpine and FR115427 were evident, a plot of the regional f values for dizocilpine and FR115427 revealed a strong overall relationship between the metabolic responses with a Pearson's product moment correlation of 0.78. In contrast, the correlation between the patterns produced by CGS19755 and that for dizocilpine or FR115427 was poor (r = 0.28 and 0.5 respectively).
最近的研究表明，竞争性和非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂可通过它们对局部脑葡萄糖利用（1CGU）的作用轻易区分开来。在本研究中，我们比较了新型NMDA拮抗剂（+）-1-甲基-1-苯基-1,2,3,4-四氢异喹啉（FR115427）对1CGU的作用，使用2-脱氧葡萄糖代谢图谱法将其代谢谱与非竞争性NMDA受体拮抗剂地佐环平（MK801）以及竞争性NMDA受体拮抗剂CGS19755的代谢谱进行比较。使用[14C]2-脱氧葡萄糖定量放射自显影术在清醒大鼠脑的80个解剖学离散区域测量局部脑葡萄糖利用。在给予FR115427（0.1 - 3毫克/千克静脉注射；n = 20）、地佐环平（0.03 - 0.3毫克/千克；n = 15）、CGS19755（1 - 30毫克/千克；n = 15）或生理盐水（2毫升/千克；n = 5）10分钟后开始研究。地佐环平使1CGU产生特征性改变，初级嗅觉和边缘区域的1CGU广泛增加，而体感和运动皮层的1CGU降低。FR115427产生的1CGU改变模式与地佐环平引发的模式大致相似，脑桥核、前扣带回和海马体中的1CGU增加，体感和运动皮层以及听觉系统各部分的1CGU降低。然而，在这方面FR115427的效力比地佐环平低约30倍。在边缘结构中，FR115427的作用不如地佐环平明显。地佐环平处理的大鼠的扣带回、梨状和内嗅皮层中1CGU增加了62 - 98%，而在给予FR115427后这些区域似乎相对未受影响。通过使用F统计量构建区域反应性层次结构，对每种药物产生的代谢反应模式进行了比较：虽然地佐环平和FR115427代谢谱的局灶性差异明显，但地佐环平和FR115427的区域F值图显示代谢反应之间存在很强的总体关系，皮尔逊积矩相关系数为0.78。相比之下，CGS19755产生的模式与地佐环平或FR115427产生的模式之间的相关性较差（r分别为0.28和0.5）。
