INHIBITION OF [H-3] (+)-MK-801 BINDING TO RAT-BRAIN SECTIONS BY CPP AND 7-CHLOROKYNURENIC ACID - AN AUTORADIOGRAPHIC ANALYSIS

1 The regional binding of [H-3]-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate ([H-3]-(+)-MK 801) to sections of rat brain was measured by an in vitro quantitative autoradiographic technique. A heterogeneous distribution of binding sites was observed. 2 High values of binding were detected in the hippocampal formation and cerebral cortex, while very low binding was found in cerebellum. [H-3]-(+)-MK 801 binding was not detectable in white matter tracts or in the brain stem. 3 [H-3]-(+)-MK 801 binding was inhibited by increasing concentrations of both 7-chlorokynurenate (1-1000 muM) and ((+)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) (0.1-100 muM). High concentrations of both drugs were able to inhibit completely specific [H-3]-(+)-MK 801 binding. 4 IC50 values calculated for both 7-chlorokynurenate and CPP-induced [3 H]-(+)-MK 801 binding inhibition were similar in all brain regions analyzed. 5 The inhibitory action of 7-chlorokynurenate and that of CPP on [H-3]-(+)-MK 801 binding were reversed by addition of glycine and glutamate respectively. 6 It is concluded that activation of glycine and N-methyl-D-aspartate (NMDA) receptors is obligatory for the binding of [H-3]-(+)-MK 801 to occur in all of the brain regions examined in the present study. Furthermore, on the basis of the similar regional sensitivities of [H-3]-(+)-MK 801 binding to the inhibitory action of 7-chlorokynurenate and CPP, a single pharmacological classification of the NMDA receptor complex in brain is suggested. The cerebellum was not included in the study due to the very low level of [H-3]-(+)-MK 801 binding detected under the experimental conditions used.