Comparison of the patterns of altered cerebral glucose utilisation produced by competitive and non-competitive NMDA receptor antagonists.
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).
Fujisawa Institute of Neuroscience in Edinburgh, Department of Pharmacology, University of Edinburgh, UK.
J
J
Sharkey
I M
IM
Ritchie
S P
SP
Butcher
J S
JS
Kelly
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects; D003847:Deoxyglucose; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005116:Extrapyramidal Tracts / Q000737:chemistry / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008032:Limbic System / Q000737:chemistry / Q000187:drug effects; D010875:Pipecolic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D044005:Tetrahydroisoquinolines
D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D044005:Tetrahydroisoquinolines; C084456:1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline; C053672:selfotel; D016291:Dizocilpine Maleate; D003847:Deoxyglucose; D005947:Glucose