Trapping Channel Block of NMDA-Activated Responses By Amantadine and Memantine THOMAS A. BLANPIED, 1 FAYE A. BOECKMAN, 2 ELIAS AIZENMAN, 2 AND JON W. JOHNSON 1 1 Department of Neuroscience, University of Pittsburgh, 15260 and 2 Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 Blanpied, Thomas A., Faye Boeckman, Elias Aizenman, and synaptic transmission and plasticity. However, PCP and ket- Jon W. Johnson. Trapping channel block of NMDA-activated amine, which also block this channel (MacDonald et al. responses by amantadine and memantine. J. Neurophysiol. 77: 1991), have severe and deleterious behavioral effects in hu- 309–323, 1997. We investigated the mechanisms by which the mans (Krystal et al. 1994; Luby et al. 1959), probably due antiparkinsonian and neuroprotective agents amantadine and mem- to their interaction with the NMDA receptor (Javitt and antine inhibit responses to N-methyl-D-aspartic acid (NMDA). Zukin 1991 ) . Finally, memantine as well blocks the NMDA- Whole cell recordings were performed using cultured rat cortical activated channel (Bormann 1989; Chen et al. 1992), but is neurons or Chinese hamster ovary ( CHO ) cells expressing NMDA currently used in the treatment of Parkinson’s disease (Fi- receptors. Both amantadine and memantine blocked NMDA-acti- scher et al. 1977), dementia (Ditzler 1991), and several vated channels by binding to a site at which they could be trapped after channel closure and agonist unbinding. For neuronal recep- movement-related disorders ( e.g., Weller and Kornhuber tors, the IC 50 s of amantadine and memantine at 067 mV were 39 1991 ) . During therapeutic use, the memantine concentra- and 1.4 mM, respectively. When memantine and agonists were tions found in cerebrospinal fluid suggest that its primary washed off after steady-state block, one-sixth of the blocked chan- site of action is the NMDA receptor (Kornhuber and Quack nels released rather than trapped the blocker ; memantine exhibited 1995), and yet it appears to induce fewer and less profound ‘‘partial trapping.’’ Thus memantine appears to have a lesser ten- effects on perception or consciousness (Ditzler 1991) than dency to be trapped than do phencyclidine or (5R,10S)-( / )-5- PCP or ketamine. The reasons for the surprisingly diverse methyl-10,11-dihydro-5H-dibenzo[1,d]cyclihepten-5,10-imine behavioral effects of blockers of the NMDA-activated chan- (MK-801). We next investigated mechanisms that might underlie partial trapping. Memantine blocked and could be trapped by re- nel are not known. It is plausible that this variation arises combinant NMDA receptors composed of NR1 and either NR2A in part from a diversity of mechanisms by which the channel or NR2B subunits. In these receptors, as in the native receptors, may be blocked. the drug was released from one-sixth of blocked channels rather To explore in detail the range of mechanisms that may than being trapped in all of them. The partial trapping we observed be exhibited by blockers of the NMDA-activated channel, therefore was not due to variability in the action of memantine on we have examined the actions on NMDA responses of mem- a heterogeneous population of NMDA receptors in cultured cortical antine and the closely related drug 1-amino-adamantane neurons. Amantadine and memantine each noncompetitively inhib- (amantadine). Amantadine is an NMDA antagonist used ited NMDA-activated responses by binding at a second site with for many of the same therapeutic purposes as memantine roughly 100-fold lower affinity, but this form of inhibition had little effect on the extent to which memantine was trapped. A (Brenner et al. 1989; Kornhuber et al. 1993; Schwab et al. simple kinetic model of blocker action was used to demonstrate 1969). It inhibits [ 3 H](5R,10S)-( / ) -5-methyl-10,11-dihy- that partial trapping can result if the presence of memantine in the dro-5H-dibenzo-cyclihepten-5,10-imine ([ 3 H]MK-801) channel affects the gating transitions or agonist affinity of the binding to human brain membrane homogenates ( Kornhuber NMDA receptor. Partial trapping guarantees that during synaptic et al. 1991) and reduces responses mediated by NMDA communication in the presence of blocker, some channels will receptors with an apparent inhibition constant greater than release the blocker between synaptic responses. The extent to memantine’s (Parsons et al. 1996). which amantadine and memantine become trapped after channel We report here that channel closure and agonist dissocia- block thus may influence their therapeutic effects and their modula- tion of NMDA-receptor-mediated excitatory postsynaptic poten- tion is permitted while either of these drugs is bound in the tials. NMDA-activated channel, resulting in trapping of the drug in the channel. This characteristic of the action of memantine and amantadine, which will be termed ‘‘trapping channel INTRODUCTION block’’ here, distinguishes them from ‘‘sequential block- ers,’’ which prevent the channel from closing while blocked A large number of ions and drugs can block the channel (Adams 1976; Antonov and Johnson 1996; Neher and of the glutamate receptor activated by N-methyl-D-aspartate Steinbach 1978 ) . Sequential and trapping channel blockers (NMDA), and the effects of these blockers are diverse. differ greatly in several ways, including the dependence of Consider, for instance, the effects of Mg 2/ , the dissociative their block at equilibrium on the agonist concentration and anesthetics phencyclidine (PCP) and ketamine, and 1- their inhibition of synaptic charge transfer. Many previously amino-3,5-dimethyladamantane ( memantine ) . The block of characterized blockers of the NMDA-activated channel act the NMDA-activated channel by extracellular Mg 2/ is criti- cal to the normal functioning of the NMDA receptor in as trapping channel blockers, including MK-801 ( Huettner 309 0022-3077/97 $5.00 Copyright  1997 The American Physiological Society J-353-6 / 9k0b$$ja11 08-13-97 18:01:31 neupa LP-Neurophys Downloaded from journals.physiology.org/journal/jn (052.073.204.196) on May 16, 2022.