Indistinguishable Synaptic Pharmacodynamics of the N-Methyl-d-Aspartate Receptor Channel Blockers Memantine and Ketamine

• DOI: 10.1124/mol.113.089334
• Publication Date: 2013-10-08T02:53:59Z
• Authors: Christine M. Emnett; Lawrence N. Eisenman; Amanda M. Taylor; Yukitoshi Izumi; Charles F. Zorumski; Steven Mennerick
• Keywords: Memantine; Postsynaptic Current

Memantine and ketamine, voltage- activation-dependent channel blockers of <i>N</i>-methyl-d-aspartate (NMDA) receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these been reported, but it is unclear whether the compounds differentially affect dynamic physiologic signaling. In this study, we explored nonequilibrium conditions relevant to synaptic transmission hippocampal networks dissociated culture slices. Equimolar memantine ketamine had indistinguishable effects on following measures: steady-state NMDA currents, NMDAR excitatory postsynaptic current (EPSC) decay kinetics, progressive EPSC inhibition during repetitive stimulation, extrasynaptic inhibition. Therapeutic drug efficacy tolerability attributed fast kinetics strong voltage dependence. However, pulse depolarization presence revealed surprisingly slow similar time course equilibration for two compounds, although produced more prominent component (62% versus 48%) re-equilibration. Simulations predicted that low gating underlies voltage–dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations efficacy. Excitatory potential–like commands only large, prolonged depolarizations unlikely be attained physiologically. fact, found no difference drugs measures spontaneous network activity or acute plasticity Despite pharmacodynamics, provided significantly greater neuroprotection damage induced oxygen glucose deprivation, consistent idea under extreme depolarizing conditions, biophysical becomes detectable. We conclude despite subtle dependence, activity, pharmacodynamics are largely independent.