COMPARISON OF COMPETITIVE AND UNCOMPETITIVE NMDA RECEPTOR ANTAGONISTSWITH REGARD TO MONOAMINERGIC NEURONAL-ACTIVITY AND BEHAVIORAL-EFFECTSIN RATS

The uncompetitive NMDA receptor antagonist, MK-801 (dizocilpine) and t he competitive NMDA receptor antagonists, CGP 37849 (DL-(E)-2-amino-4- methyl-5-phosphono-3-pentenoic acid) and its ethyl ester CGP 39551, we re compared with respect to behavioural and neurochemical effects in h andling-habituated rats. Dopamine, serotonin and their precursors and metabolites were determined in 14 brain regions. Furthermore, adrenali ne and noradrenaline were analysed in regional brain tissue. When MK-8 01 and CGP 37849 were administered at doses which induced similar amph etamine-like behavioural effects (hyperlocomotion, stereotypies), both drugs produced comparable increases in dopamine and serotonin metabol ism in various brain regions, thus strongly indicating that these neur ochemical 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 serot onin 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-l ike behavioural adverse effects were much less intense and dopamine an d serotonin metabolism was not altered in most brain regions. In addit ion to effects on dopaminergic and serotonergic systems, all three dru gs induced changes in adrenaline and/or noradrenaline levels in some b rain regions. The data demonstrate that competitive NMDA receptor anta gonists, such as CGP 37849, produce activation of dopaminergic and ser otonergic pathways similar to that caused by uncompetitive NMDA recept or antagonists, provided that behaviourally equipotent doses are admin istered.