COMPARISON OF THE PATTERNS OF ALTERED CEREBRAL GLUCOSE-UTILIZATION PRODUCED BY COMPETITIVE AND NONCOMPETITIVE NMDA RECEPTOR ANTAGONISTS

Recent studies indicate that competitive and non-competitive NMDA rece ptor antagonists can be readily distinguished by their effects on loca l cerebral glucose utilisation (1CGU). In the present study we compare the effects of the novel NMDA antagonist, (+)-1-methyllphenyl-1,2,3,4 -tetrahydroisoquinoline (FR115427) on 1CGU, comparing its metabolic pr ofile with that of the non-competitive NMDA receptor antagonist, dizoc ilpine (MK801) and of the competitive NMDA receptor antagonist CGS1975 5, using the 2-deoxyglucose metabolic mapping approach. Local cerebral glucose utilisation was measured in 80 anatomically discrete regions of the conscious rat brain using [C-14]2-deoxyglucose quantitative aut oradiography. Studies were initiated IO min after the administration o f 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). Dizoc ilpine produced characteristic alterations in 1CGU with widespread inc reases in 1CGU in primary olfactory and limbic areas while reducing 1C GU in somatosensory and motor cortex. FR115427 produced a pattern of a ltered 1CGU which was broadly similar to that elicited by dizocilpine with increases in 1CGU in the pontine nuclei, presubiculum and hippoca mpus and reductions in somatosensory and motor cortex and within compo nents of the auditory system. However, FR115427 was approximately 30-f old less potent than dizocilpine in this regard. In limbic structures, the effects of FR115427 were less pronounced than those produced by d izocilpine. Increases in 1CGU of 62-98% were found in retrosplenial, p iriform and entorhinal cortex of dizocilpine-treated rats whereas thes e areas appeared relatively unaffected following FR115427 administrati on. 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 betwe en the patterns produced by CGS19755 and that for dizocilpine or FR115 427 was poor (r = 0.28 and 0.5 respectively).