DIFFERENT BINDING AFFINITIES OF NMDA RECEPTOR-CHANNEL BLOCKERS IN VARIOUS BRAIN-REGIONS - INDICATION OF NMDA RECEPTOR HETEROGENEITY

The N-methyl-D-aspartate (NMDA) receptor-channel complex exists in mul tiple forms which probably have different physiological and pharmacolo gical properties. To further evaluate this concept of different NMDA r eceptor subtypes, receptor binding and autoradiographic techniques wer e used to study the phencyclidine (PCP) binding site of the NMDA recep tor ion-channel complex. [H-3]MK-801 was employed to characterize bind ing properties of (+)-MK-801, (-)-MK-801, phencyclidine (PCP), (+/-)-k etamine, amantadine (1-amino-adamantane) and memantine (3,5-dimethyl-1 -amino-adamantane) in different brain regions. Saturation experiments on homogenized membranes revealed the existence of single classes of b inding sites in cortex and cerebellum but with significant different a ffinities between these regions (K-D/Cortex = 4.59 nM, B-max/Cortex = 0.836 pmol/mg protein; K-D/Cereb = 25.99 nM, B-max/Cereb = 0.573 pmol/ mg protein) suggesting that the lower affinity in cerebellum indicates another population of NMDA receptor channels. In contrast, in striatu m there was clear evidence for two binding sites (K-D/high = 1.43 nM, B-max/high = 0.272 pmol/mg protein; K-D/high = 12.15 nM, B-max/low = 1 .76 pmol/mg protein). Displacement studies (autoradiography and bindin g) revealed a lower affinity for unlabeled (+)-MK-801 in striatum whic h was clearly not the case for memantine. In cerebellar membranes ther e was a significant decrease in the affinity for both MK-801 enantiome rs and PCP but not for the 1-amino-adamantanes. In contrast, all compo unds showed lowered affinity in the dentate gyrus. These findings supp ort NMDA receptor heterogeneity which may be of particular relevance f or the development of subtype-selective drugs.