Trapping channel block of NMDA-activated responses by amantadine and memantine. Blanpied, Thomas A., Faye Boeckman, Elias Aizenman, and Jon W. Johnson. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260 and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
APStracts 3:0209N, 1996.
We investigated the mechanisms by which the antiparkinsonian and neuroprotective agents amantadine and memantine inhibit responses to N-methyl- d-aspartic acid (NMDA). Whole-cell recordings were performed using cultured rat cortical neurons or Chinese hamster ovary (CHO) cells expressing NMDA receptors. Both amantadine and memantine blocked NMDA-activated channels by binding to a site at which they could be trapped following channel closure and agonist unbinding. For neuronal receptors, the IC50's of amantadine and memantine at -67 mV were 39 [mu]M and 1.4 [mu]M, respectively. When memantine and agonists were washed off following steady-state block, 1/6 of the blocked channels released rather than trapped the blocker; memantine exhibited "partial trapping." Thus, memantine appears to have a lesser tendency to be trapped than do phencyclidine (PCP) or (5R,10S)-(+)-5-methyl-10,11-dihydro-5H- dibenzo[1,d]cyclihepten-5,10-imine (MK-801). We next investigated mechanisms that might underlie partial trapping. Memantine blocked and could be trapped by recombinant NMDA receptors composed of NR1 and either NR2A or NR2B subunits. In these receptors, as in the native receptors, the drug was released from 1/6 of blocked channels rather than being trapped in all of them. The partial trapping we observed therefore was not due to variability in the action of memantine on a heterogeneous population of NMDA receptors in cultured cortical neurons. Amantadine and memantine each noncompetitively inhibited NMDA-activated responses by binding at a second site with roughly 100-fold lower affinity, but this form of inhibition had little effect on the extent to which memantine was trapped. A simple kinetic model of blocker action was used to demonstrate that partial trapping can result if the presence of memantine in the channel affects the gating transitions or agonist affinity of the NMDA receptor. Partial trapping guarantees that during synaptic communication in the presence of blocker, some channels will release the blocker between synaptic responses. The extent to which amantadine and memantine become trapped after channel block thus may influence their therapeutic effects and their modulation of NMDA receptor-mediated EPSPs.

Received 29 April 1996; accepted in final form 29 August 1996.
APS Manuscript Number J353-6.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 7 October 1996