PT  - JOURNAL ARTICLE
AU  - Christine M Emnett (Wroge)
AU  - Lawrence Eisenman
AU  - Amanda M Taylor
AU  - Yukitoshi Izumi
AU  - Charles F. Zorumski
AU  - Steven J. Mennerick
TI  - Indistinguishable Synaptic Pharmacodynamics of the NMDAR Channel Blockers Memantine and Ketamine
AID  - 10.1124/mol.113.089334
DP  - 2013 Oct 07
TA  - Molecular Pharmacology
PG  - mol.113.089334
4099  - http://molpharm.aspetjournals.org/content/early/2013/10/07/mol.113.089334.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/10/07/mol.113.089334.full
AB  - Memantine and ketamine, voltage- and activation-dependent channel blockers of NMDA receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these blockers have been reported, but it is unclear whether the compounds differentially affect dynamic physiological signaling. Here we explored non-equilibrium conditions relevant to synaptic transmission in hippocampal networks in dissociated culture and hippocampal slices. Equimolar memantine and ketamine had indistinguishable effects on the following measures: steady-state NMDA currents, NMDAR EPSC decay kinetics, progressive EPSC inhibition during repetitive stimulation, and extrasynaptic NMDAR inhibition. Therapeutic drug efficacy and tolerability of memantine have been attributed to fast kinetics and strong voltage dependence. However, pulse depolarization in drug presence revealed a surprisingly slow and similar time course of equilibration for the two compounds, although memantine produced a more prominent fast component (62 vs. 48%) of re-equilibration. Simulations predicted that low gating efficacy underlies the slow voltage-dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations of gating efficacy. EPSP-like voltage commands produced drug differences only with large, prolonged depolarizations unlikely to be attained physiologically. In fact, we found no difference between drugs on measures of spontaneous network activity or acute effects on plasticity in hippocampal slices. Despite indistinguishable synaptic pharmacodynamics, ketamine provided significantly greater neuroprotection from damage induced by oxygen glucose deprivation, consistent with the idea that under extreme depolarizing conditions, the biophysical difference between drugs becomes detectable. We conclude that despite subtle differences in voltage dependence, during physiological activity, blocker pharmacodynamics are largely indistinguishable and largely voltage independent.