TRAPPING CHANNEL BLOCK OF NMDA-ACTIVATED RESPONSES BY AMANTADINE AND MEMANTINE

We investigated the mechanisms by which the antiparkinsonian and neuro protective agents amantadine and memantine inhibit responses to N-meth yl-D-aspartic acid (NMDA). Whole cell recordings were performed using cultured rat cortical neurons or Chinese hamster ovary (CHO) cells exp ressing NMDA receptors. Both amantadine and memantine blocked NMDA-act ivated channels by binding to a site at which they could be trapped af ter channel closure and agonist unbinding. For neuronal receptors, the IC(50)s of amantadine and memantine at -67 mV were 39 and 1.4 mu M, r espectively. When memantine and agonists were washed off after steady- state block, one-sixth of the blocked channels released rather than tr apped the blocker; memantine exhibited ''partial trapping.'' Thus mema ntine appears to have a lesser tendency to be trapped than do phencycl idine or 0,11-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 c omposed of NR1 and either NR2A or NR2B subunits. In these receptors, a s in the native receptors, the drug was released from one-sixth of blo cked channels rather than being trapped in all of them. The partial tr apping we observed therefore was not due to variability in the action of memantine on a heterogeneous population of NMDA receptors in cultur ed cortical neurons. Amantadine and memantine each noncompetitively in hibited NMDA-activated responses by binding at a second site with roug hly 100-fold lower affinity, but this form of inhibition had little ef fect on the extent to which memantine was trapped. A simple kinetic mo del of blocker action was used to demonstrate that partial trapping ca n result if the presence of memantine in the channel affects the gatin g transitions or agonist affinity of the NMDA receptor. Partial trappi ng guarantees that during synaptic communication in the presence of bl ocker, some channels will release the blocker between synaptic respons es. The extent to which amantadine and memantine become trapped after channel block thus may influence their therapeutic effects and their m odulation of NMDA-receptor-mediated excitatory postsynaptic potentials .