Preferential location of N-methyl-D-aspartate (NMDA) receptors on postsynaptic membranes and on non-noradrenergic nerve terminals of the rat brain cortex

Summary The effect of DSP4-induced destruction of noradrenergic neurones on ³H-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (³H-CPP) binding to N-methyl-D-aspartate (NMDA) receptors and on ³H-desipramine (³H-DMI) binding to the neuronal noradrenaline carrier was investigated in rat brain cortex buffy coat membranes. ³H-DMI bound with high affinity to a single site at the neuronal noradrenaline carrier (K_D = 5.26 ± 1.67 nmol/l) whereas the binding of ³H-CPP to the NMDA receptor was of intermediate affinity (K_D = 274 ± 45 nmol/l). Fourteen days after a single-dose treatment with DSP4 (1) the B_max value for ³H-DMI binding was reduced by 74%, (2) the B_max value for ³H-CPP binding only tended to be decreased (by 24%; not statistically significant), (3) the endogenous noradrenaline content was reduced by 70% compared to untreated controls and, (4) the absolute amount of the NMDA-evoked ³H-noradrenaline overflow but not the fractional release was reduced by 55%. It is concluded that in the rat cerebral cortex presynaptic NMDA-receptors on noradrenergic nerve endings, which have previously been detected in release experiments with NMDA on cortical synaptosomes preincubated with ³H-noradrenaline, cannot be identified in radioligand binding experiments. Obviously, the cerebral cortical NMDA receptors are predominantly located on postsynaptic neuronal membranes and potentially on non-noradrenergic nerve terminals as well.Send offprint requests to M. Gothert at the above address