MODULATION BY BOTH DIPHENYLIODONIUM AND DIPHENYLENEIODONIUM OF [H-3] MK-801 BINDING TO RAT-BRAIN SYNAPTIC-MEMBRANES

Binding of 0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) was significantly inhibited by the addition of several different comp ounds related to generation of nitric oxide (NO) at 100 mu M in rat br ain synaptic membranes. These included sodium nitroprusside, diphenyli odonium (DI), diphenyleneiodonium (DPI) and methylene blue. However, n either S-nitroso-N-acetyl-penicillamine nor S-nitroso-L-glutathione in hibited binding at 100 mu M. Both DI and DPI inhibited binding in a co ncentration-dependent manner at a concentration range of over 1 mu M, while further addition of spermidine (SPD) significantly attenuated th e potency of DPI to inhibit binding without affecting that of DI. In c ontrast, SPD induced significant potentiation of the ability of unlabe lled MK-801 to displace [H-3]MK-801 binding in a fashion sensitive to antagonism by the novel polyamine antagonist bis-(3-aminopropyl)nonane diamine. This novel polyamine antagonist also prevented the reversing effect of SPD on inhibition by DPI of [H-3]MK-801 binding. Moreover, D PI competitively exacerbated the ability of SPD to potentiate [H-3]MK- 801 binding in the presence of both L-glutamic acid and glycine at max imally effective concentrations. On the other hand, SPD was effective in reversing the inhibition by DPI in cerebellar, but not hippocampal, synaptic membranes. These results suggest that both DI and DPI may mo dulate synaptic responses mediated by the N-methyl-D-aspartate recepto r through inhibition of opening processes of the ion channel in a mann er irrespective of generation of NO radicals in particular situations. Possible involvement of the polyamine domain in the inhibition by DPI is also suggested. (C) 1997 Elsevier Science Ltd.