Comparison of competitive and uncompetitive NMDA receptor antagonists with regard to monoaminergic neuronal activity and behavioural effects in rats

Abstract

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 CGPer 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.